Bone cement comprising a bone cement softener for reducing vertebral fractures

Abstract

The present invention relates to a bone cement for the use in a method for reducing the occurrence of vertebral fractures following vertebral augmentation therapy. The method is characterized by injecting a poly(methyl methacrylate) (PMMA)-based bone cement comprising a bone cement softener into at least one vertebra of a subject in need 5 thereof. The method maintains vertebral height and is especially suitable for the reduction of adjacent vertebral fractures in an osteoporotic spine.

Description

[0001] Bone cement comprising a bone cement softener for reducing vertebral fractures Technical field

[0002] The present invention relates to the use of a polymethyl methacrylate (PMMA) based bone cement comprising a softener for the reduction of adjacent vertebral fractures in an osteoporotic spine.

[0003] Background

[0004] A spinal fracture is a compression or structural failure of the vertebrae and can occur anywhere along the spine. Most spinal fractures are caused from injury or trauma from car accidents, falls, sports or high velocity impacts.

[0005] A compression fracture occurs when one or more vertebrae in the spine collapse, resulting in a reduction in the height of the affected vertebrae. Compression fractures commonly occur in the thoracic and lumbar regions of the spine and are often the result of conditions that weaken the bones, such as osteoporosis, trauma, or metastatic cancer.

[0006] Both men and women are diagnosed with vertebral compression fractures. The incidence of clinically diagnosed vertebral compression fractures in women (123 / 100,000 patient years) is comparable to that for hip fractures, with fracture pain usually lasting from two weeks to three months, associated with intense, deep, and sometimes intractable pain. Each additional new vertebral compression fracture is associated with a further increase in functional limitation, of a magnitude similar to that in patients with diabetes, ischemic heart disease and rheumatism.

[0007] Women with a prevalent vertebral fracture have significantly lower quality of life than women without a prevalent vertebral fracture and exhibit a 15% higher mortality.

[0008] Severe kyphosis is strongly predictive of pulmonary deaths, plausibly because those with underlying lung disease and decreased respiratory reserves may not tolerate restrictive changes in thoracic anatomy resulting from vertebral fractures.

[0009] Vertebral augmentation is a well-established technique that has been reported to provide significant relief to patients with painful vertebral compression fractures related to osteoporosis. Immediate improvement in the quality of life follows the reduction of pain. Moreover, the mobility of elderly patients is crucial to reduce the risk of thrombotic events, pulmonary complications and decubitus ulcers. The immediate pain relief is likely to allow patients to resume their normal activity much quicker than if they are treated conservatively.

[0010] PMMA

[0011] Poly(methyl methacrylate) (PMMA), also known as poly(methacrylic acid methyl ester), is a bioinert material commonly used to repair and augment spinal compression fractures and to fixate hip and knee implants. Cancellous bone, also known as trabecular bone, is a porous, low-density structure that provides mechanical support and shock absorption within vertebral bodies and other skeletal regions. Since PMMA has a Young’s modulus that is much higher than that of human cancellous bone, it may affect the biomechanics negatively, which may promote fractures in the tissues adjacent to the augmented vertebrae.

[0012] The use of PMMA-based bone cement has been common in orthopaedic surgeries for decades and is well-established and considered safe. In addition, it is relatively inexpensive compared to alternative materials, making it an attractive material, especially in healthcare systems with limited resources.

[0013] PMMA-based bone cement is generally well-tolerated by the body, and allergic reactions are rare, which makes it suitable for use in orthopaedic surgeries. It can be modified with additives such as antibiotics to reduce the risk of infection or with radiocontrast agents to improve visibility during surgery. Addition of a radiocontrast is radiopaque, meaning it appears clearly on X-rays and other imaging modalities, it enables surgeons to assess the placement and integrity of implants and bone cement during and after surgery.

[0014] PMMA based bone cement is easy to mix and manipulate, allowing surgeons to quickly fill voids such as in osteoporotic vertebrae and anchor implants. Its paste-like consistency allows for good flow into bone cavities and defects and around implants before it hardens. It provides immediate mechanical stability upon curing. This stability helps to support the weight and function of the affected vertebrae.

[0015] As PMMA based bone cement generates heat during the curing process, it can potentially damage surrounding tissues, particularly in cases where large volumes of cement are used or during prolonged curing times. Both vertebroplasty, kyphoplasty and other implant supported vertebral augmentation have been used successfully for stabilizing painful vertebral compression fractures. Concerns have been raised about use of poly(methyl methacrylate) (PMMA) based bone cements for these procedures since the high compressive modulus of elasticity (E) of the cement is thought to be one of the causes of the higher number of adjacent-level vertebral fractures. In addition, when using a traditional, high modulus PMMA-based bone cement, the treated vertebra exhibit a markedly higher stiffness compared to neighbouring vertebrae, which may lead to post-operative complications, such as refractures of the treated vertebrae or fractures in adjacent vertebrae.

[0016] A polydimethylsiloxane based bone cement may be an option but it is more expensive and difficult to apply, with procedures taking ~40 min as opposed to 10-15 min with conventional PMMA bone cements.

[0017] Vertebroplasty or kyphoplasty of osteoporotic vertebrae using a traditional PMMA based bone cement results in a vertebrae with a higher modulus compared to the surrounding vertebrae, which can cause post-operative problems, such as fractures. In severe cases, compressed vertebrae can lead to compression of the spinal cord or nerve roots, resulting in neurological symptoms such as weakness, numbness, or tingling in the limbs, bowel or bladder dysfunction, and difficulty walking. Once a vertebra has been compressed, treated or non-treated, there is an increased risk of further fractures in the spine, particularly in individuals with osteoporosis or other conditions that weaken the bones.

[0018] Thus, there is an urgent need to reduce adjacent fractures in compressed vertebrae after a vertebroplasty or kyphoplasty and to be able to maintain the vertebrae height over time in treated patients, using a well-established and safe PMMA based bone cement.

[0019] Chemical modification of the material would give the possibility to control its Young’s modulus. Hypotheses that chemically modified PMMA bone cement with a lower Young’s modulus would be beneficial to reduce fractures have been made. However, surprisingly, such results has not been shown in practice even though the use of PMMA bone cement in itself is a well-established.

[0020] Summary

[0021] It is a general objective of this invention to provide PMMA-based bone cements for use in a method for reducing the occurrence of vertebral fractures following vertebral augmentation therapy, characterized by injecting a PMMA-based bone cement comprising a bone cement softener into at least one vertebra of a subject.

[0022] The bone cements as used herein are made from a number of components which are described elsewhere herein. These together make up a composition which according to the invention may be used in a therapeutic and partially surgical method to reduce the occurrence of subsequent vertebral fractures.

[0023] It is another objective of this invention to provide a method of performing vertebral augmentation therapy with a reduced risk of new vertebral fractures, comprising injecting at least one vertebra with a PMMA-based bone cement comprising a bone cement softener, The vertebral augmentation therapy may be administered to a subject in need thereof thereby reducing the risk of new vertebral fractures.

[0024] It is yet another objective of this invention to provide a method of protecting vertebrae against new vertebral fractures in a subject undergoing vertebral augmentation therapy comprising injecting at least one vertebra with PMMA-based bone cement comprising a bone cement softener.

[0025] It is a further objective of this invention to provide a method of protecting the spine against new vertebral fractures comprising injecting at least one vertebra with a PMMA-based bone cement comprising a bone cement softener.

[0026] Detailed description

[0027] In a first aspect, the present disclosure relates to a poly(methyl methacrylate) (PMMA)-based bone cements for use in a method of reducing the occurrence of vertebral fractures following vertebral augmentation therapy, characterized by injecting a PMMA-based bone cement comprising a bone softener into at least one vertebra of a subject. The PMMA based bone cement comprising a bone softener is the subject of the present invention.

[0028] Medical conditions

[0029] Osteoporosis is a bone disease that develops when bone mineral density and bone mass decreases, or when the structure and strength of bone changes. This can lead to a decrease in bone strength that can increase the risk of fractures. When the vertebrae in the spine weaken from osteoporosis, they can become flatter. The vertebra can collapse during normal activity, leading to a spinal fracture. This type of compression fracture can cause a great deal of pain and can permanently alter the shape and strength of the spine. Spinal fractures due to osteoporosis often occur while doing something that causes relatively minor trauma to the spine, such as an insignificant fall, or twisting while lifting.

[0030] Osteoporosis primarily affects the elderly, particularly postmenopausal women as oestrogen, which plays a protective role in bone health, decreases significantly after menopause. However, men can also develop osteoporosis as they age. Other risk factors include a family history of the condition, certain medications, low body weight, smoking, excessive alcohol consumption, and a sedentary lifestyle. Patients showing a DEXA T-score below -2.5 would be classified as having osteoporosis. A DEXA T-score represents the number of standard deviations by which an individual’s bone mineral density differs from the mean value of a healthy young reference population, as determined by dual-energy X-ray absorptiometry (DEXA).

[0031] Osteopenia is a medical condition characterized by lower than normal bone mineral density, which is not as severe as osteoporosis. It indicates that bones are weaker than normal and an increased risk of fractures but not to the extent found in osteoporosis. Patients showing a DEXA T-score between -1 and -2.5 would be classified as having osteopenia.

[0032] In one aspect or embodiment, the present invention relates to a method to reduce the occurrence of vertebral fractures following vertebral augmentation therapy, wherein the at least one vertebra is osteopenic or osteoporotic. In another aspect or embodiment, the at least one vertebra exhibits an osteopenic or osteoporotic bone structure

[0033] In another aspect or embodiment, the invention relates to a method to reduce the occurrence of vertebral fractures following vertebral augmentation therapy wherein the subject suffers from osteopenia or osteoporosis.

[0034] In another aspect or embodiment, the present invention relates to a method to reduce the occurrence of vertebral fractures following vertebral augmentation therapy, wherein the subject has a bone density DEXA test T-score below -1 , such as below -2.5. In some aspects or embodiments, the disclosed bone cement for the use is injected in a subject exhibiting a pain intensity of at least 40 mm on the Visual Analogue Scale (VAS) prior to treatment.

[0035] The Visual Analogue Scale (VAS) is a validated instrument used to quantify pain intensity, typically consisting of a 100 mm horizontal line between two anchors, that describe “no pain” (0 mm) “worst imaginable pain” (100 mm). The patient marks a point on the line corresponding to their perceived pain intensity, which is then measured in millimeters from the “no pain” anchor. A VAS score of at least 40 mm indicates moderate to severe pain, representing a clinically meaningful threshold for intervention in patients with vertebral compression fractures.

[0036] In another aspect or embodiment, the disclosed bone cement for the use is injected in a subject exhibiting a pain intensity of at least 4 on the Numeric Pain Rating Scale (NPRS) prior to treatment.

[0037] The Numeric Pain Rating Scale (NPRS) is a standardized 11 -point scale ranging from 0 (“no pain”) to 10 (“worst possible pain”), used to assess subjective pain intensity. A score of 4 or higher on the NPRS reflects moderate to severe pain that typically requires clinical management. In one aspect the present invention relates to a method to reduce the occurrence of vertebral fractures following vertebral augmentation therapy wherein the at least one vertebra is fractured due to low impact trauma. Low impact fractures, also known as, low-energy, low-level or fragility fractures, are fractures that result from mechanical forces that would not ordinarily result in a fracture, such as falling from a standing position or from the height of a few steps. These injuries are common among patients who, for some reason, have decreased bone density or a weak bone structure.

[0038] A stable fracture is a bone fracture with minimal damage. The ends of the bones line up, nearly matching, allowing for easier healing than with more severe fractures. In another aspect or embodiment, the present invention relates to a method to reduce the occurrence of vertebral fractures following vertebral augmentation therapy, wherein the at least one vertebra has a stable fracture. A stable fracture is a bone fracture with minimal damage, in which the ends of the bones remain aligned or nearly aligned, thereby allowing for easier healing compared to more severe fractures. Multiple myeloma is a blood cancer that develops in plasma cells in the bone marrow Myeloma cells stimulate osteoclasts activation, the cells responsible for bone resorption, which leads to increased bone breakdown. Simultaneously, osteoblasts are inhibited, hence leading to less bone formation. This imbalance leads to osteolytic lesions that weaken the bone. Fractures commonly occur in the spine.

[0039] Hemangiomas are benign vascular tumors that can occur in the spine. The tumors can grow and cause the affected vertebra to weaken. The weakening can lead to structural instability of the spine and eventually vertebral compression fractures.

[0040] In one aspect the present invention relates to a method to reduce the occurrence of vertebral fractures following vertebral augmentation therapy wherein the subject suffers from multiple myeloma and / or hemangioma.

[0041] In one aspect or embodiment , the present invention relates to a method to reduce the occurrence of vertebral fractures following vertebral augmentation therapy in a subject, wherein the subject is a human male or female.

[0042] In another aspect or embodiment, the present invention relates to a method to reduce the occurrence of vertebral fractures following vertebral augmentation therapy in a subject, wherein the subject has vertebral augmentation therapy performed on any one or more of the vertebrae T5 to L5. These vertebral levels represent the region of the spine most commonly affected by osteoporotic or pathological compression fractures due to their load-bearing function and transitional position between the thoracic and lumbar segments.

[0043] In yet another aspect or embodiment, the present invention relates to a method to reduce the occurrence of vertebral fractures following vertebral augmentation therapy in a subject, wherein the subject is at least 30 years, such as at least 40 years, such as at least 50 years, such as at least 60 years, such as at least 70 years, such as at least 80 years.

[0044] PMMA-based bone cement comprising a softener

[0045] The PMMA-based bone cement comprising a softener for vertebral augmentation therapy can be obtained by mixing liquid components and powder components, wherein the liquid components comprise a liquid cement component and a liquid softener. The liquid and powder components can be mixed in any sequential order as long as the components are thoroughly mixed to form an extrudable paste. The PMMA based bone cement comprising a softener for vertebral augmentation therapy can be obtained by mixing a liquid component and a powder component, wherein the liquid component comprises a liquid cement component and a liquid softener. The liquid component may conveniently be provided in one vial with all liquid components or in two separate vials with softener and liquid MMA respectively.

[0046] The liquid component comprises methacrylic acid methyl ester monomers, an activator such as benzenamine, N,N,4-trimethyl and a radical initiator such as 1 ,4-dihydoroxy benzene. The liquid component further comprises a liquid softener such as linoleic acid. The liquid component is mixed with a powder component. The powder component comprises partially pre-polymerized PMMA, a radical initiator, preferably benzoyl peroxide, and a radiocontrast agent, preferably zirconium dioxide or barium sulphate. The bone cement composition can further comprise other polymers in addition to PMMA and drugs such as antibiotics.

[0047] The PMMA of the bone cement initially comprises both monomers of methacrylic acid methyl ester in the liquid component, and partially pre-polymerized PMMA in the powder component. Upon mixing the polymerisation process is initiated.

[0048] In one aspect or embodiment, the present invention relates to a PMMA-based bone for use in a. method for reducing the occurrence of vertebral fractures following vertebral augmentation therapy, wherein the PMMA-based bone cement comprises a liquid component and a powder component, wherein the liquid component comprises a liquid cement component and a liquid softener.

[0049] In one aspect or embodiment of the present invention, the liquid cement component of said PMMA-based bone cement comprises poly(methacrylic acid methyl ester) or methyl methacrylate , benzenamine, N,N,4-trimethyl and 1 ,4-dihydoroxy benzene.

[0050] In one aspect or embodiment, the bone cement comprises a liquid component that includes methyl methacrylate (MMA) monomer, N,N-dimethyl-p-toluidine (DMPT), and mequinol (MeHQ). DMPT acts as an accelerator or co-initiator that promotes free-radical polymerization in the presence of a peroxide initiator, typically benzoyl peroxide (BPO) contained in the powder component. In certain or embodiments, a lower volumetric percentage of DMPT may be employed, which may also influence the amount of softening agent required to achieve the desired handling and mechanical properties. MeHQ functions as a polymerization inhibitor or stabilizer to prevent premature polymerization during storage and handling of the liquid cement component. Alternatively, the liquid component of the bone cement may comprise hydroquinone instead of MeHQ. The use of hydroquinone as an inhibitor provides a similar stabilizing effect to mequinol but may offer improved control of polymerization kinetics, particularly under elevated temperature or long-term storage conditions.

[0051] Radiopacifiers are added to bone cements to enhance their visibility under radiographic imaging. This visibility ensures accurate application, facilitates postoperative monitoring, helps in the early detection of complications, and ultimately contributes to the overall safety and success of vertebral augmentation therapy. Suitable radiopacifiers include, but are not limited to, zirconium dioxide, barium sulfate and strontium salts. In another aspect or embodiment of the present invention, the powder component of said PMMA based bone cement comprises PMMA, zirconium dioxide and dibenzoyl peroxide and optionally a copolymer such as polystyrene.

[0052] In another aspect or embodiment of the present invention, the powder component of said PMMA based bone cement comprises PMMA, barium sulphate and dibenzoyl peroxide and optionally a copolymer such as polystyrene.

[0053] The inclusion of styrene in the powder component serves to modify the mechanical and thermal properties of the cured bone cement. Styrene may act as a copolymer or modifier that reduces brittleness and alters the stiffness of the polymer matrix, thereby contributing to a more compliant and energy-absorbing material. In addition, the incorporation of styrene may influence the polymerization kinetics and exothermic behavior during curing, lowering peak polymerization temperatures and improving handling characteristics.

[0054] The bone cement composition may further comprise one or more additional polymers in combination with PMMA to modify its mechanical or handling properties. Suitable polymers may include, for example, copolymers of methyl methacrylate, hydroxyethyl methacrylate, or other biocompatible acrylic or methacrylic polymers. The composition may also incorporate pharmacologically active agents, such as antibiotics, anti- resorptive agents, or analgesics, to provide localized drug delivery at the implantation site.

[0055] In one aspect or embodiment of the present invention, the liquid softener of said PMMA-based bone cement is linoleic acid.

[0056] In another aspect or embodiment of the present invention, the liquid softener of said PMMA-based bone cement is selected from linoleic acid, ricinoleic acid, oleic acid, methyl linoleate, castor oil, linseed oil, and / or tung oil, preferably linoleic acid.

[0057] Linoleic acid is an unsaturated fatty acid commonly found in plant oils such as sunflower or safflower oil. In the context of the present disclosure, linoleic acid and related organic fatty acids, esters, or natural oils act as softening agents within the PMMA matrix, serving as plasticizers that modify the mechanical and handling properties of the bone cement. These agents can be incorporated into the liquid monomer phase or dispersed within the polymer powder prior to mixing. As a result, the cured cement exhibits a lower elastic modulus and greater compliance, better replicating the mechanical behaviour of cancellous bone and reducing stress concentrations at the bone-cement interface. In one aspect or embodiment of the present invention, the liquid cement component of said PMMA-based bone cement comprises 90-99.9% (v / v) methacrylic acid methyl ester, 0.1-5% (v / v) benzenamine, N,N,4-trimethyl and 30-85 ppm 1 ,4-dihydoroxy benzene.

[0058] In another aspect or embodiment of the present invention, the powder component of said PMMA-based bone cement comprises 50-60% (w / w) PMMA, 40-55% (w / w) zirconium dioxide and 0.5-1.5% (w / w) dibenzoyl peroxide.

[0059] In yet another aspect or embodiment of the present invention, the powder component of said PMMA-based bone cement comprises 60-80% (w / w) PMMA, 20-40% (w / w) barium sulfate and 0.5-1.5% (w / w) dibenzoyl peroxide.

[0060] In one aspect or embodiment of the present invention, the liquid softener of said PMMA-based bone cement constitutes 1-20% (v / v) of the liquid component, such as 1-5% (v / v), such as 1-10% (v / v), such as 5-10% (v / v), such as 10-15% (v / v), such as 10-20% (v / v), such as 15-20% (v / v). The liquid softener may constitute 1-25% (v / v) of the liquid component, such as between 5-20% (v / v), such as 8-16%. In one aspect or embodiment of the present invention, the PMMA based bone cement comprises 1-10% (v / w) liquid softener such as 1-6 % or 2-6% (v / w) liquid softener, such as such as 2-4 % (v / w), such as 2-5% (v / w), such as 3-5% (v / w). In some embodiments less than 1% can be used.

[0061] In one aspect or embodiment of the present invention, the liquid cement component of said PMMA base bone cement comprises 98.6% (v / v) methacrylic acid methyl ester, 1.4% (v / v) benzenamine, N,N,4-trimethyl and 50 ppm 1 ,4-dihydoroxy benzene.

[0062] In one aspect or embodiment of the present invention, the powder cement component of said PMMA-base bone cement comprises 54.2% (w / w) PMMA, 45% (w / w) zirconium dioxide and 0.8% (w / w) dibenzoyl peroxide.

[0063] In another aspect or embodiment of the present invention the powder cement component of said-PMMA base bone cement comprises 70% (w / w) PMMA, 30% (w / w) barium sulfate and 0.8% (w / w) dibenzoyl peroxide.

[0064] In one aspect or embodiment of the present invention, the cement softener of said PMMA based bone cement is added to the liquid component in an amount corresponding to at least 12% (v / v) of the liquid component.

[0065] In another aspect or embodiment of the present invention, said PMMA-based bone cement comprises 1-8% (v / w) liquid softener, such as 2-5% (v / w), such as 3,7% (v / w) liquid softener.

[0066] In yet another or embodiment of the present invention, the PMMA in the powder component is partially pre-polymerized.

[0067] In a further aspect or embodiment of the present invention, the liquid cement component and the powder component of said PMMA-based bone cement are present in a 1 :2.6 ratio.

[0068] The another aspect or embodiment, the liquid cement component and the powder component of the PMMA-based bone cement is between 1 :1.5 and 1 :3.5, preferably between 1 :2 and 1 :3.

[0069] In another aspect or embodiment of the present invention, the liquid cement component and the powder component of said PMMA-based bone cement are present in a 1 :2.3 ratio. In one or embodiment of the present disclosure, said PMMA-based bone cement and a bone cement softening agent results in low-modulus bone cement.

[0070] Low-modulus bone cements are formulations designed to exhibit reduced stiffness compared to conventional PMMA-based cements, thereby improving mechanical compatibility with natural bone. By lowering the elastic modulus, these cements can better absorb and distribute physiological loads, reducing stress concentrations at the bone-cement interface and minimizing the risk of bone resorption or implant loosening.

[0071] The modified bone cement has a stiffness matched to normal trabecular bone (~700MPa); a low setting temperature (below 40°C) and a longer injection time (up to 15 minutes), which gives improved injectability. The bone cement has a viscosity allowing for application using a cannula, while at the same time enabling the operator to control the distribution of the cement inside the vertebra suitable for performing vertebral augmentation procedures.

[0072] In one aspect of the present invention, said PMMA-based bone cement for use comprising a bone cement softener results in a low-modulus bone cement.

[0073] In another aspect or embodiment of the present invention, said PMMA-based bone cement for use comprising a bone cement softener has an elastic modulus below 2000 MPa, such as below 1500 MPa, preferably below 1000 MPa, even more preferably below 800 MPa.

[0074] In one aspect or embodiment of the present invention, said PMMA-based bone cement has a compression strength of 28.3±5.1 MPa 24 hours after mixing

[0075] The polymerization of the present bone cement occurs at a lower temperature (<40°C) compared to standard PMMA based bone cement (>60°C), hence reducing the amount of temperature induced tissue damages. The standard ASTM 451 states max 90°C.

[0076] In one aspect or embodiment of the present invention, said PMMA based bone cement comprising a bone cement softener has a setting temperature below 40°C.

[0077] The polymerization of the present bone cement occurs at a significantly lower temperature, typically below 40 °C, compared to conventional PMMA-based bone cements, which often reach exothermic temperatures above 60 °C. In some embodiments the polymerization temperature may be even lower, such as below 37°C, or even below 30°C. This lower polymerization temperature minimizes the risk of thermally induced tissue damage at the bone-cement interface and improves overall biocompatibility. According to ASTM F451 and ISO 5833 standards, the polymerization temperature of bone cement should remain below the threshold that may cause tissue injury, with ASTM F451 specifying a maximum exothermic temperature of 90 °C. ASTM F451 and ISO 5833 are internationally recognized standards that define the physical, mechanical, and thermal requirements for acrylic bone cements to ensure their safety, biocompatibility, and clinical performance in surgical applications.

[0078] In one aspect or embodiment of the present invention, said PMMA based bone cement has an injection time window of up to 25 minutes, such as up to 20 minutes, such as up to 19 minutes, such as up to 18 minutes, such as up to 17 minutes, such as up to 15 minutes.

[0079] In one aspect or embodiment of the present invention, said PMMA based bone cement has an injection time window of up to 15 minutes.

[0080] Examples of suitable softened cements for use according to the disclosure include:

[0081] Table 1. PMMA based bone cement comprising a bone cement softener (percentages add up to 100 of each component liquid softener as percentage of the two liquid components).

[0082] Powder component

[0083] PMMA 14.1 g (54.2%)

[0084] Zirconium dioxide 11.7 g (45%)

[0085] Dibenzoyl peroxide 0.2 g (0.8%)

[0086] Liquid component

[0087] MMA 9.9 ml (98.6%)

[0088] Benzenamine, N,N,4-trimethyl 0.1 ml (1.4%)

[0089] 1 ,4-dihydoroxy benzene 50 ppm

[0090] Liquid softener

[0091] Linoleic acid 1.4 ml (12% of 11,4 ml)

[0092]

[0093] Table 2. PMMA based bone cement comprising a bone cement softener and barium sulfate as a radiopacifier.

[0094] PMMA based bone cement comprising a cement softener (BaSO4)

[0095] Powder component

[0096] PMMA 12.3 g (68,4%)

[0097] Barium sulfate 5.4 g (30%)

[0098] Dibenzoyl peroxide 0.28 g (1 ,6%)

[0099] Liquid component

[0100] MMA 8.23 ml (99,1%)

[0101] Benzenamine, N,N,4-trimetyl 0.07 ml (0,9%)

[0102] Hydroquinone 75 ppm

[0103] Liquid softener

[0104] Linoleic acid 0.75-1.5 ml

[0105]

[0106] Vertebral augmentation procedures

[0107] Kyphoplasty involves the insertion of one or more bone tamps into the fractured vertebral body through a small incision in the back. Once the bone tamp is in place, it is inflated to create a cavity within the fractured vertebra, restoring some of its height and reducing the deformity caused by the compression fracture. After the cavity is created, the bone tamp is deflated and removed, and a bone cement is injected into the cavity to stabilize the fractured vertebra and provide structural support.

[0108] The neck has seven cervical vertebrae, each designated C1-C7. Below these are the 12 thoracic vertebrae, designated T1-T12. The lower back contains the lumbar vertebrae, numbered L1-L5. The sacrum is formed by the fusion of five sacral vertebrae.

[0109] Vertebroplasty involves percutaneous injection of bone cement into a fractured vertebral body through a small incision in the skin. Prior to the injection, the surgeon uses imaging guidance (such as fluoroscopy or computed tomography) to accurately position a needle within the fractured vertebra. Once the needle is properly positioned, bone cement is injected into the fractured vertebra, where it quickly hardens and stabilizes the bone. Apart from analgesic medicine, physiotherapy, rest or a spinal orthosis, kyphoplasty and vertebroplasty, involving injecting a bone cement into a vertebra, can be a feasible option to many patients to stabilize the spine and reduce pain. However, one of the drawbacks with standard kyphoplasty and vertebroplasty is the development of adjacent fractures in the non-treated vertebrae.

[0110] The goal of kyphoplasty surgery is to relieve pain, restore lost vertebral body height, and stabilize the fracture. The procedure involves the insertion of two inflatable bone tamps (IBTs), into the vertebrae. The IBTs are inflated under volumetric control, reducing the fracture and pushing the endplates apart, thereby partially restoring vertebral height and correcting angular deformity. The newly formed cavity is filled with bone cement after IBT removal.

[0111] Vertebroplasty is also used to treat spinal compression fractures. During the procedure, bone cement is injected directly into the fractured vertebra to stabilize it, relieve pain, and restore mobility.

[0112] Both kyphoplasty and vertebroplasty are minimally invasive procedures and usually take about 1-2 hours. In clinical practice, the choice of administration procedure, kyphoplasty or vertebroplasty depends on many factors including but not limited to the investigator’s preference and familiarity with a given procedure, location and degree of the compression fracture. Current mortality data is in favour of kyphoplasty, thus unless there is a vertebrae plana kyphoplasty should be prioritized whenever possible over vertebroplasty. The primary benefits of kyphoplasty over traditional vertebroplasty include the ability to restore vertebral height and reduce spinal deformity, which can significantly improve posture and reduce pain.

[0113] In one aspect or embodiment the present invention, the vertebral augmentation therapy involves kyphoplasty or vertebroplasty.

[0114] In another aspect or embodiment of the present invention, the vertebral augmentation therapy involves injecting 3-8 ml PMMA based bone cement, such as 4-6 ml, such as preferably 5 ml.

[0115] Post-therapy fractures

[0116] Adjacent vertebral fracture is a frequent and severe complication in patients suffering from osteoporotic vertebral compression fractures having undergone percutaneous vertebroplasty or percutaneous kyphoplasty, which results in poor long-term outcome and recurrence of pain-related symptoms.

[0117] Treatment of vertebral compression fractures through intravertebral injection of PMMA-based bone cement by either vertebroplasty or kyphoplasty, results in an immediate pain relief although potential side effects such as exothermal nerve damage and increased risk of future fractures of adjacent vertebrae may limit the usefulness. Since PMMA has a significant modulus mismatch with adjacent vertebrae, that may lead to increased stresses at the augmented / non-augmented junction. The current standard PMMA cements have a much higher elastic modulus (-3000 MPa) than that of the surrounding vertebral bone (10-900 MPa), meaning that they are stiffer than bone, which could pose a risk of provoking adjacent fractures.

[0118] It has been reported that the relative risk of developing new vertebral compression fracture at the level adjacent to an augmented level is 4.62 times greater than at a non-adjacent level.

[0119] Adjacent fractures resulting from kyphoplasty or vertebroplasty using a high modulus bone cement usually appears shortly after treatment, typically within three months. Adjacent fractures appearing later than three months are most likely caused by the progression of osteoporosis in the patient and would most likely have occurred irrespective of the kyphoplasty or vertebroplasty.

[0120] Re-fractures of kyphoplasty or vertebroplasty treated vertebra is a rare condition, however it does occur.

[0121] Non-adjacent fracture are generally considered not to be a direct result of the kyphoplasty or vertebroplasty, but are considered to be caused by the general progression of osteoporosis in the patient. Surprisingly, the use of the bone cement softener of the present invention shows positive results on the occurrence of non-adjacent fractures.

[0122] In one aspect or embodiment of the present invention, the occurrence of adjacent vertebral fractures are reduced.

[0123] In another aspect or embodiment of the present invention, the occurrence of non-adjacent vertebral fractures are reduced. In yet another aspect or embodiment of the present invention, the occurrence of vertebral re-fractures are reduced.

[0124] In one aspect or embodiment of the present invention, the occurrence of adjacent vertebral fractures are reduced by at least 60% up to 3 months following vertebral augmentation therapy. In another aspect of the present invention, the occurrence of adjacent vertebral fractures are reduced by at least 40% after up to 3 months following vertebral augmentation therapy.

[0125] In yet another aspect or embodiment of the present invention, the occurrence of adjacent vertebral fractures are reduced by at least 20% after up to 3 months following vertebral augmentation therapy.

[0126] In a further aspect or embodiment of the present invention, the occurrence of non-adjacent vertebral fractures are reduced by up to 100%.

[0127] In one aspect or embodiment of the present invention, less than 20% of all subjects experience adjacent and non-adjacent fractures within three months following vertebral augmentation therapy.

[0128] In another aspect or embodiment of the present invention, less than 10% of all subjects experience adjacent and non-adjacent fractures within three months following vertebral augmentation therapy.

[0129] In yet another aspect or embodiment of the present invention, less than 5% of all subjects experience adjacent and non-adjacent fractures within three months following vertebral augmentation therapy.

[0130] In a further aspect or embodiment of the present invention, less than 2% of all subjects experience adjacent and non-adjacent fractures within three months following vertebral augmentation therapy.

[0131] The clinical characteristics of VCFs are loss of vertebral height and acute pain.

[0132] Procedures like vertebroplasty or kyphoplasty, where the fractured vertebra is stabilized and filled with bone cement aim to regain the vertebral height. By restoring vertebral height through vertebroplasty or kyphoplasty, the compression on nerves and surrounding tissues is alleviated, reducing pain. In one aspect or embodiment of the present invention, said vertebral augmentation therapy maintains vertebral height.

[0133] In another aspect or embodiment of the present invention, said vertebral augmentation therapy maintains the vertebral height for up to 12 months.

[0134] In yet another aspect or embodiment of the present invention, said vertebral augmentation therapy maintains the vertebral height for up to 24 months.

[0135] Osteoporosis in the spine can be very painful and managing pain associated with osteoporosis involves a multifaceted approach aimed at alleviating discomfort, preventing further bone damage, and improving overall quality of life.

[0136] Physical therapy can help improve mobility, strength, and flexibility, reducing pain and minimizing the risk of falls and fractures. Orthotic devices such as braces, splints, or orthopaedic footwear can provide support and stability to weakened bones, reducing pain and preventing further injury. These devices may be particularly beneficial for individuals with spinal compression fractures or postural abnormalities. Analgesic drugs can also be administered to reduce pain. Both kyphoplasty and vertebroplasty can effectively reduce back pain and improve the quality of life for patients suffering from fractures relating to osteoporosis.

[0137] One of the primary goals of vertebral augmentation, such as kyphoplasty and / or implant supported vertebral augmentation is to restore vertebral height and realign the fractured vertebra, which helps to relieve pressure on surrounding nerves, muscles, and other structures in the spine. By restoring vertebral height, vertebral augmentation can reduce the exaggerated forward curvature of the spine (kyphosis) commonly seen in individuals with vertebral compression fractures, thus improving spinal alignment and posture.

[0138] The mechanism of action of vertebroplasty is the stabilization of the fractured vertebra using bone cement. By injecting bone cement into the fractured vertebra, vertebroplasty provides immediate structural support and stability, preventing further collapse and displacement of bone fragments. Vertebroplasty does not typically restore vertebral height or correct spinal deformity. However, by stabilizing the fractured vertebra and preventing further collapse, vertebroplasty can indirectly alleviate pain associated with vertebral compression and spinal deformity. Other post-therapy outcomes

[0139] In one aspect or embodiment of the present invention, the lower back (T5 to L5) pain in a subject is below 100 on the Visual Analog Scale (VAS) such as below 50, such as below 30, such as below 20, such as preferably below 10, directly after vertebral augmentation therapy.

[0140] In another aspect or embodiment of the present invention, the lower back (T5 to L5) pain in a subject is below 100 on the VAS scale such as below 50, such as below 30, such as below 20, such as preferably below 10, five days after vertebral augmentation therapy.

[0141] In yet another aspect or embodiment of the present invention, the lower back (T5 to L5) pain in a subject is below 100 on the VAS scale such as below 50, such as below 30, such as below 20, such as preferably below 10, three months after vertebral augmentation therapy.

[0142] In a further aspect or embodiment of the present invention, the lower back (T5 to L5) pain in a subject is below 100 on the VAS scale such as below 50, such as below 30, such as below 20, such as preferably below 10, one year after vertebral augmentation therapy.

[0143] In a further aspect or embodiment of the present invention, the lower back (T5 to L5) pain in a subject is below 100 on the VAS scale such as below 50, such as below 30, such as below 20, such as preferably below 10, two years after vertebral augmentation therapy.

[0144] In one aspect or embodiment of the present invention, the lower back pain (T5 to L5) in a subject is reduced to below 10 on the Numeric Pain Rating Scale (NPRS) scale, such as below 5, such as below 4, such as below 3, such as preferably below 2, directly after vertebral augmentation therapy.

[0145] In another aspect or embodiment of the present invention, the lower back pain (T5 to L5) in a subject is reduced to below 10 on the NPRS scale, such as below 5, such as below 4, such as below 3, such as preferably below 2, five days a after vertebral augmentation therapy. In yet another aspect or embodiment of the present invention, the lower back pain (T5 to L5) in a subject is reduced to below 10 on the NPRS scale, such as below 5, such as below 4, such as below 3, such as preferably below 2, three months after vertebral augmentation therapy.

[0146] In a further aspect or embodiment of the present invention, the lower back pain (T5 to L5) in a subject is reduced to below 10 on the NPRS scale, such as below 5, such as below 4, such as below 3, such as preferably below 2, one year after vertebral augmentation therapy.

[0147] In yet a further aspect or embodiment of the present invention, the lower back pain (T5 to L5) in a subject is reduced to below 10 on the NPRS scale, such as below 5, such as below 4, such as below 3, such as preferably below 2, two years after vertebral augmentation therapy.

[0148] Lower back pain caused by fractured vertebrae can be severely debilitating for the affected patient. The Oswestry Disability Index (ODI) has become one of the principal condition-specific outcome measures used in the management of spinal disorders. The ODI is a validated, 10-point patient-reported outcome questionnaire. It is considered the ‘gold standard’ for measuring disability and quality of life impairment for adults with low back pain. The ODI can be used to assess both chronic and acute conditions of varying severity. It has high test-retest reliability and takes around 5 min for a patient to complete. Not only is it straightforward to administer and score, but it can also be used in a variety of clinical settings to assess baseline function and postintervention outcomes.

[0149] In one aspect or embodiment of the present invention, the Oswestry Disability Index (ODI) in a subject is below 50, such as below 40, such as below 30, such as below 20, such as preferably below 10, five days after vertebral augmentation therapy.

[0150] In another aspect or embodiment of the present invention, the ODI in a subject is below 50, such as below 40, such as below 30, such as below 20, such as preferably below 10, three months after vertebral augmentation therapy.

[0151] In yet another aspect or embodiment of the present invention, the ODI in a subject is below 50, such as below 40, such as below 30, such as below 20, such as preferably below 10, one year after vertebral augmentation therapy. In a further aspect or embodiment of the present invention, the ODI in a subject is below 50, such as below 40, such as below 30, such as below 20, such as preferably below 10, two years after vertebral augmentation therapy.

[0152] Vertebral augmentation is a well-established technique that has been reported to provide significant relief to patients with painful vertebral compression fractures related to osteoporosis. Immediate improvement in the quality of life follows the reduction of pain. Moreover, the mobility of elderly patients is a crucial to reduce the risk of thrombotic events, pulmonary complications and decubitus ulcers. The immediate pain relief is likely to allow patients to resume their normal activity much quicker than if they are treated conservatively.

[0153] Vertebral augmentation results in immediate and significant pain relief in more than 80% of the patients with osteoporotic vertebral compression fractures. It appears that the pain relief is maintained also during long-term follow-up. Vertebral augmentation has been reported to also lead to improvement in quality of life and spine related mobility as well as reduction of pain medication usage. Physical inactivity caused by pain can severely impact the patient’s ability to perform activities of daily living and prolonged bed-rest can in some instances increase the risk of medical complications. In one aspect or embodiment of the present invention, the Quality of Life assessed by the Short Form 12 Physical Component Summary (SF12 PCS) in a subject is above 50, such as above 60, such as above 70, such as above 80, such as preferably above 90, five days after vertebral augmentation therapy.

[0154] In another aspect or embodiment of the present invention, the Quality of Life assessed by the Short Form 12 Physical Component Summary (SF12 PCS) in a subject is above 50, such as above 40, such as above 30, such as above 20, such as preferably above 10, three months after vertebral augmentation therapy.

[0155] In yet another aspect or embodiment of the present invention, the Quality of Life assessed by the Short Form 12 Physical Component Summary (SF12 PCS) in a subject is above 50, such as above 40, such as above 30, such as above 20, such as preferably above 10, one year after vertebral augmentation therapy.

[0156] In a further aspect or embodiment of the present invention, the Quality of Life assessed by the Short Form 12 Physical Component Summary (SF12 PCS) in a subject is above 50, such as above 40, such as above 30, such as above 20, such as preferably abovelO, two years after vertebral augmentation therapy.

[0157] In one aspect, the present invention relates to a method of performing vertebral augmentation therapy with a reduced risk of new vertebral fractures. The method comprises injecting at least one vertebra of a subject in need of vertebral augmentation therapy with a polymethyl methacrylate (PMMA)-based bone cement comprising a bone cement softening agent.

[0158] In another aspect, the invention provides a method of protecting vertebrae against new vertebral fractures in a subject undergoing vertebral augmentation therapy. The method comprises injecting a PMMA-based bone cement comprising a bone cement softener into at least one vertebra, such that the modified mechanical properties of the cured cement distribute physiological loads more evenly along the spinal column, enhancing post-procedural spinal integrity and reducing the incidence of adjacent level fractures.

[0159] In a further aspect, the invention encompasses a method of protecting the spine as a whole against new vertebral fractures by administering a PMMA-based bone cement formulation that includes a bone cement softener to at least one affected vertebral body requiring vertebral augmentation.

[0160] In yet another aspect, the invention relates to a method of performing vertebral augmentation therapy comprising injecting between approximately 4 and 8 milliliters of a PMMA-based bone cement comprising a bone cement softening agent into at least one vertebra of a subject in need thereof.

[0161] Examples

[0162] Example 1. Influence of composition on polymerization behaviour and mechanical performance

[0163] To evaluate the influence of compositional parameters on the handling and mechanical characteristics of different bone cement formulations, a comparative analysis was performed using several commercially available PMMA-based bone cements, as listed in Table 5. Formulations containing higher amounts of benzoyl peroxide (BPO) as the polymerization initiator (approximately 1.6-2.0%) exhibited a faster polymerization rate, with shorter setting times of about 15-18 minutes (Table 4). When the BPO concentration was reduced to 0.5-0.9%, polymerization proceeded more slowly, resulting in longer setting times of up to 59 minutes. This demonstrated that the initiator concentration directly governs the polymerization rate and working time of the cement. A comparable trend was observed with the accelerator benzenamine, N,N,4-trimethyl (also known as N,N-dimethyl-p-toluidine or DMPT) (Table 3, liquid component).

[0164] Formulations containing higher DMPT levels (approximately 1.1-1.4%) exhibited faster initiation and correspondingly higher polymerization temperatures (approximately 35-36 °C, Table 4). In contrast, cements with lower DMPT levels (0.6-0.9%) showed a milder exothermic reaction, with peak polymerization temperatures as low as 27-30 °C, providing a safety advantage by minimizing the risk of thermally induced bone or tissue damage during vertebral augmentation.

[0165] The composition of the polymer in the powder phase also played a significant role. Cements based solely on PMMA exhibited higher viscosity and stiffness, whereas those containing methyl methacrylate along with a styrene co-polymer demonstrated lower viscosity, reduced polymerization temperature, and a lower compressive modulus (ranging from 677 to 867 MPa, Table 5).

[0166] Notably, formulations containing lower concentrations of BPO and DMPT required smaller volumes of the cement softener (linoleic acid) to achieve comparable handling and mechanical performance. This trend can be seen when comparing for example, compositions B and C, where the powder and liquid formulations are almost identical except for their BPO content. Increasing the amount of BPO leads to faster polymerization, and because the softener interferes with this process, less softener is required when the BPO content is reduced. This pattern is further confirmed by Teknimed F20, which contains an even lower proportion of BPO and correspondingly requires a smaller amount of softener in the final formulation.

[0167] Similarly, the concentration of DMPT influences the required amount of softener. When comparing compositions B and C, the latter has a lower volumetric percentage of DMPT, which may contribute to a reduced need for linoleic acid. This relationship also helps explain why V-Steady™, despite containing a lower percentage of BPO, still requires 1.4 mL of softener. Table 3. Composition of representative PMMA-based bone cement formulations V- A B D E

[0168] Component Chemical C

[0169] composition Steady™ % (w / w) % (w / w) % (w / w) % (w / w) % (w / w)

[0170] % (w / w)

[0171] Poly (methyl

[0172] methacrylate) 54.16 % 68.40% - - 68.1% 19.20% (PMMA)

[0173] Methyl

[0174] methacrylate - - - - styrene 68.00% 69.10% 35.30% copolymer

[0175] Powder Benzoyl

[0176] component 0.84 %

[0177] peroxide 1.60% 2.00% 0.90% 1.90% 0.50% Zirconium - - - dioxide (ZrCte) 45.00 % 45.00% Barium sulphate - 30.00% 30.00% 30.00% 30.00% - Weight of

[0178] powder 26g 18g 20g 20g 20g 25.8g Methyl

[0179] methacrylate 98.6 % 99.10% 99.10% 99.40% 98.90% 99.30% (MMA)

[0180] Benzenamine,

[0181] N,N,4-trimethyl

[0182] (N,N-dimethyl- 1.4 % 0.90% 0.90% 0.60% 1.10% 0.70% Liquid p-toluidine,

[0183] component DM PT)

[0184] Methyl ether of

[0185] hydroquinone 50 ppm - - - - - (MeHQ)

[0186] 1,4-dihydoroxy - benzene 50 ppm 75 ppm 75 ppm 79 ppm 20 ppm Amount of liquid 10 ml 8.3 g 9g 9g 8.9 g 9.2 g Cement Linoleic acid

[0187] Softener (purity > 99%) 1.4ml 1.4ml 1.4ml 1.0ml 1.4ml 0.196ml

[0188]

[0189] Table 4. Physical and handling when mixed with softener.

[0190] Handling V- A B C D E

[0191] Properties Steady™

[0192]

[0193] 24 ± 1 15 ± 1 18 ± 2 59.2 ± 2.0 Setting time 15 ± 1 min - min min min min Maximum

[0194] 36 ± 1 28 ± 3 27.1 ± 1.0 polymerization 35 ± 1SC 29 ± 2SC -SCSCSC

[0195] temperature

[0196]

[0197] - : Properties not tested.

[0198] Table 5. Mechanical properties when mixed with softener

[0199] Mechanical V- A B C D E

[0200] Properties Steady™

[0201] Compressive 756 ± 16 860 ± 30 858 ± 867 ± 52 677 ± 42 750 ± 150 Modulus MPa MPa 40 MPa MPa MPa MPa Static strength 24 ± 1 31 ± 1 31 ± 1 29 ± 1 35 ± 7

[0202] 39 ± 2 MPa

[0203] (Compressive) MPa MPa MPa MPa MPa

[0204]

[0205] Example 2. Preparing the bone cement

[0206] A commercial bone cement, V-Steady™ (G21 S.r.l. , San Possidonio, Italy) was used as control (VS) to be modified with the additive, linoleic acid (LA). The modified (low modulus) cement is referred to as VS-LA. For both cements, the powder is comprised of pre-polymerized PMMA beads, benzoyl peroxide, and zirconium dioxide (ZrO2) and the liquid is comprised of methyl methacrylate monomer, N,N-di-methyl-p-toluidine, and hydroquinone. The only difference in composition between the two cements is that, for the low-modulus cement, 12 vol% of LA was pre-blended with the liquid. The VS was prepared according to the manufacturer’s instructions for use by mixing the powder and the liquid manually in a glass mortar with a spatula for 30-45 sec at room temperature. The VS-LA was prepared by adding 12 vol% linoleic acid in the liquid and mixing it until dissolved in a centrifuge tube and then mixing the powder and the modified liquid manually in glass mortar with a spatula for 30-45 sec at room temperature (Table 4). Table 6. PMMA based bone cement comprising a bone cement softener

[0207] Powder component

[0208] PMMA 14.1 g (54.2%)

[0209] Zirconium dioxide 11.7 g (45%)

[0210] Dibenzoyl peroxide 0.2 g (0.8%)

[0211] Liquid component

[0212]

[0213] MMA 9.9 ml (98.6%)

[0214] Benzenamine, N,N,4-trimethyl 0.1 ml (1.4%)

[0215] 1 ,4-dihydoroxy benzene 50 ppm

[0216] Liquid softener

[0217] Linoleic acid 1.4 ml (12%)

[0218]

[0219] Example 3. Surgical procedure and injected volume

[0220] In clinical practice, the choice of one administration procedure over the other (kyphoplasty or vertebroplasty) depends on many factors including, but not limited to, the investigator’s preference and familiarity with a given procedure, insurance coverage, and the location and degree of the compression fracture. Current mortality data favour kyphoplasty; thus, unless there is a vertebrae plana, balloon kyphoplasty is prioritized whenever possible over vertebroplasty.

[0221] The mean injected volume of the PMMA-based bone cement, prepared as described in example 1 , was 5.1 mL ± 2.0 mL (with a range of 1.5-16.0 mL), while the control PMMA group demonstrated a mean injected volume of 4.8 mL ± 1.3 mL (with a range of 2.0-8.0 mL).

[0222] Table 7. Surgical procedure and injected volume

[0223] Active group (V- Control group Flex), n=99 (V-Steady), n= 102 Volume Material n 81 85

[0224] Injected Mean (SD) 5.1 (2.0) 4.8 (1.3)

[0225] Median (Min, Max) 5.0 (1.5, 16.0) 5.0 (2.0, 8.0) Surgery Type Kyphoplasty 67 (67.7%) 74 (72.5%)

[0226] Vertebroplasty 18 (18.2%) 16 (15.7%) Missing data 14 (14.1%) 12 (11.8%)

[0227]

[0228] Example 4. Post vertebral augmentation hospitalization

[0229] The date and time of hospital admission and discharge were recorded for each subject. The number of hospital bed days was defined as the number of nights spent in hospital from the day of surgery through Day 7 post-procedure. If discharge occurred after seven days, the number of bed days during the first week was recorded as seven. Among subjects treated with the inventive PMMA-based composite bone cement (Active group, n = 97), the mean number of hospital bed days during the first week was 2.3 ± 3.1 , with a median of 1 day (Q1-Q3: 0-3 days). For subjects treated with standard PMMA cement (Control group, n = 96), the mean was 2.0 ± 2.4, with a median of 1 day (Q1-Q3: 0-3 days). The maximum stay was 12 days for the Active group nd 11 days for the Control group.

[0230] Both treatment groups demonstrated short hospitalization times, typically one to three days, indicating rapid postoperative recovery following vertebral augmentation. Use of the PMMA-based composite bone cement comprising a softening agent did not increase hospitalization duration and was associated with procedural safety comparable to standard PMMA cement.

[0231] Table 8. Number of hospital bed days during the first week post vertebral augmentation

[0232] Variable Active group (V- Control group Flex), n=101 (V-Steady), n= 102 Number of n 97 96

[0233] Days, Hospital Mean (SD) 2.3 (0.0, 3.0) 2.0 (2.4)

[0234] Median (Q1, Q3) 1.0 (0.0, 3.0) 1.0 (0.0, 3.0) Min, Max 0.0, 12.0 0.0, 11.0

[0235] Number of 0 38 (39.2%) 36 (37.5%) hospital bed 1 24 (24.7%) 18 (18.8%)

[0236] days 2 4 (4.1%) 8 (8.3%)

[0237] 3 7 (7.2%) 12 (12.5%)

[0238] 4 7 (7.2%) 6 (6.3%)

[0239] 5 1 (1.0%) 6 (6.3%)

[0240] 6 3 (3.1%) 5 (5.2%)

[0241] >7 13 (13.4%) 5 (5.2%)

[0242] Number of n

[0243] hospital bed Mean (SD)

[0244] days during the Median (Q1, Q3)

[0245] first week* Min, Max

[0246]

[0247] * If the subject was discharged after 7 days, number of hospital bed days during first week is counted as 7. Denominator for percentage is number of subjects with non-missing data

[0248] Example 5. Quality of life

[0249] The Oswestry Disability Index (ODI) is a standardized questionnaire used to assess the degree of disability and functional impairment in individuals with low back pain. It is considered one of the most comprehensive and widely used tools for this purpose. The ODI helps in evaluating the impact of low back pain on a person's ability to manage everyday life activities. The ODI is used in both clinical practice and research to monitor the progress of patients undergoing treatment for low back pain; evaluate the effectiveness of various interventions; help in the decision-making process regarding treatment plans and facilitate communication between healthcare providers and patients regarding the impact of back pain on daily life.

[0250] Scores from 0% to 20% indicate minimal disability; 20% to 40%, moderate disability; 40% to 60%, severe disability; 60% to 80%, crippled; and 80% to 100%, bedbound or exaggerating their symptoms.

[0251] Table 9. Oswestry Disability Index (ODI) soft bone cement

[0252] Active group (V-Flex), n=101

[0253] Observed value Change from baseline Scheduled n Mean (SD) Median (Min, n Mean (SD) Median (Min, time point Max) Max) Screening 93 65.7 (21.7) 66.7 - - - (Visit 1) (18, 100)

[0254] Day 1 98 34.1 (22.1) 37.8 92 -32.1 (35.1) -20.1 (Visit 2) (0, 76) (-100, 29) Day 89 87 21.7 (21.9) 15.6 81 -45.9 (34.7) -42.0 (Visit 4) (0, 82) (-100, 29) Day 364 34 23.3 (21.4) 15.8 32 -35.9 (27.5) -28.9 (Visit 5) (0, 67) (-94, 3)

[0255]

[0256] Table 10. Oswestry Disability Index (ODI) standard bone cement

[0257] Control group (V-Steady), n=102

[0258]

[0259] Observed value Change from baseline Scheduled n Mean (SD) Median (Min, n Mean (SD) Median time point Max) (Min, Max) Screening 94 66.7 67.3 - - - (Visit 1) (21.3) (20, 100)

[0260] Day 1 100 36.6 38.0 92 -32.9 (36.9) -31.1 (Visit 2) (24.7) (0, 93) (-100, 58) Day 89 87 23.5 16.0 79 -43.6 (34.8) -44.4 (Visit 4) (22.8) (0, 88) (-100, 20) Day 364 42 24.3 23.1 41 -36.7 (30.8) -40.0 (Visit 5) (20.5) (0, 84) (-98, 17)

[0261]

[0262] Pain scale - VAS

[0263] The Visual Analogue Scale (VAS) measures pain intensity. The VAS consists of a 10cm line, with two end points representing Omm (‘no pain’) and 100mm (‘pain as bad as it could possibly be’). The patient is sked to rate their current level of pain by placing a mark on the line. Use a ruler to measure the distance in centimetres from the ‘no pain marker’ (or zero) to the current pain mark.

[0264] Pain scale - NPRS

[0265] The Numerical Pain Rating Scale (NPRS) is a subjective measure in which patients rate their pain on an eleven-point numerical scale. The scale is composed of 0 (no pain at all) to 10 (worst imaginable pain).

[0266] Table 11. Pain assessment using VAS or NPRS - Soft bone cement

[0267] Active group (V-Flex), n=101

[0268] Observed value Change from baseline Score Scheduled n Mean Median n Mean Median time point (SD) (Min, (SD) (Min, Max) Max) VAS Screening 49 76.6 80.0 - - - (Visit 1) (16.2) (40, 100)

[0269]

[0270] Day 1 48 67.5 70.0 46 -9.4 0.0 (Visit 2) (22.4) (20, 100) (17-6) (-70, 20) Before 49 37.6 30.0 45 -36.4 -30.0 discharge (26.8) (0, 90) (30.4) (-97, 21) from hospital

[0271] Day 5 37 33.2 30.0 33 -38.1 -37.0 (Visit 3) (23.5) (0, 90) (23.2) (-100, 3) Day 89 (Visit 35 33.7 30.0 32 -42.1 -45.5 4) (26.7) (0, 90) (27.5) (-95, 10) Day 364 13 35.0 40.0 13 -45.0 -40.0 (Visit 5) (25.3) (0, 60) (26.3) (-90, -10) NPRS Screening 44 8.4 9.0 - - - (Visit 1) (1-5) (4, 10)

[0272] Day 1 44 8.3 9.0 39 -0.1 0.0 (Visit 2) (1-6) (4, 10) (0.8) (-4, 2) Before 45 2.9 2.0 41 -5.7 -7.0 discharge (2.6) (0, 8) (3.4) (-10, 0) from hospital

[0273] Day 5 60 2.6 2.0 42 -6.2 -8.0 (Visit 3) (2.7) (0, 9) (3.4) (-10, 3) Day 89 (Visit 53 1.5 0.0 38 -7.1 -9.0 4) (2.6) (0, 10) (3.2) (-10, 1) Day 364 21 2.2 1.0 14 -4.5 -4.0 (Visit 5) (2.7) (0, 8) (3.5) (-10, 0)

[0274]

[0275] Table 12. Pain assessment using VAS or NPRS - Standard bone cement

[0276] V-Steady group, n=102

[0277] Observed value Change from baseline Score Scheduled n Mean (SD) Median Median time point (Min, Mean (Min,

[0278] Max) n (SD) Max) VAS Screening 51 75.6 (17.8) 80.0 (8, - - - (Visit 1) 100)

[0279]

[0280] Day 1 49 68.3 (22.0) 70.0 (8, 46 -4.3 0.0 (Visit 2) 100) (22.5) (-70, 82) Before 48 46.2 (25.3) 50.0 (0, 46 -29.5 -30.0 discharge 90) (33.2) (-88, 82) from hospital

[0281] Day 5 35 37.1 (24.5) 40.0 (0, 35 -40.0 -45.0 (Visit 3) 90) (28.3) (-88, 14) Day 89 (Visit 36 28.9 (25.1) 20.5 (0, 34 -48.1 -60.0 4) 80) (28.8) (-90, 10) Day 364 16 32.0 (26.7) 35.0 (0, 15 -40.4 -40.0 (Visit 5) 80) (41.1) (-100, 52) NPRS Screening 49 8.6 9.0 - - (Visit 1) (1-6) (4, 10)

[0282] Day 1 47 8.3 9.0 43 -0.3 0.0 (Visit 2) (1-8) (1, 10) (1-3) (-7, 1) Before 45 2.9 2.0 41 -5.7 -7.0 discharge (2.8) (0, 10) (3.3) (-9, 0) from hospital

[0283] Day 5 65 2.8 2.0 48 -6.3 -8.0 (Visit 3) (3.0) (0, 10) (3.5) (-10, 2) Day 89 (Visit 51 2.1 1.0 41 -6.6 -8.0 4) (2.5) (0, 9) (3.3) (-10, 2) Day 364 26 0.9 0.5 19 -6.6 -6.0 (Visit 5) (1-1) (0, 3) (1-9) (-9, -2)

[0284]

[0285] Quality of life - SF PCS 12

[0286] The SF PCS 12 (Short From - Physical Component Study - 12 questions) is a selfreported outcome measure assessing the impact of health on an individual's everyday life. It is often used as a quality of life measure. The survey concerns limitations in physical activities because of health problems; limitations in social activities because of physical or emotional problems; limitations in usual role activities because of physical health problems; bodily pain; general mental health (psychological distress and wellbeing); limitations in usual role activities because of emotional problems; vitality (energy and fatigue) and general health perceptions Scores range from 0 to 100, with higher scores indicating better physical and mental health functioning. A score of 50 or less on the PCS-12 has been recommended as a cut-off to determine a physical condition.

[0287] Table 13. Quality of life assessment - SF12 PCS - 1 year interim data

[0288] Number of subjects V-flex Control V-flex Control Total Number of women 29 27 56 Number of men 6 8 14 Total no patients 35 35 70 SF12 PCS

[0289] SF12 Pre-op (Visit 1) 33 32 13 14 27 Day 5 (Visit 2) 33 35 13 13 26 3 months (Visit 3) 42 40 11 9 20 1 year (Visit 4) 34 29 1 1 2

[0290]

[0291] Example 6. Imaging fractures

[0292] For assessing spinal osteoporotic fractures, both the antero-posterior (AP) and lateral projections of both thoracic and lumbar spines was performed. On the initial exam, the AP view of the thoracic spine demonstrated C7 to L1 levels and the AP of the lumbar spine, also including T12 to S1. The AP radiographs allowed for identification of the correct vertebral levels, and also contributed to detection of vertebral deformities and incidental findings that may mimic fracture when only a lateral image is available. The lateral thoracic spine demonstrated T4 to L1 levels. The lateral lumbar spine view demonstrated T12 to S1. Radiological imaging was used to evaluate if any clinically significant changes, such as refractures had occurred post-operatively in the treated, adjacent or remote vertebras as compared with baseline if the patient experience acute or significant increased pain during the study. An independent radiographic review was performed to avoid bias. Any clinically significant new or worsening spinal pathology was recorded and the Investigator assessed whether or not the fracture was related to the vertebral augmentation therapy. X-ray was used to assess occurrence of vertebral height of the treated vertebra as well as vertebral fractures, refractures and adjacent fractures.

[0293] The ability of the PMMA based bone cement comprising a softener to fill and stabilize the vertebra was documented through radiographic controls using X-ray performed immediately post administration and at specific time points during (0, 12, 24 months). The images were assessed for vertebral height, the occurrence of adjacent fractures, and the occurrence of non-adjacent fractures. The assessments was done in comparison with baseline images. Vertebral height is defined as the anterior and posterior height of the vertebra as measured from the Antero-Posterior and Lateral directions.

[0294] MRI was used to verifying an ongoing fracture process and the level of the fractured vertebra. CT scan was performed if no MRI imaging had been done was done prior to inclusion in the clinical investigation. Together with Bone Scan, CT was used to document disease activity, distribution and to exclude metastasis.

[0295] CT scans were performed after the procedure (< 24 hours) to document any extravasation of the injected bone cement. A 1-year follow-up CT-scan was done to document vertebral height compared to baseline and detection of new fractures.

[0296] Table 14. Fractures recorded during the first 3 months.

[0297] V-Flex V-Steady

[0298] Events / n (%) Events / n (%)

[0299] All fractures Total 4 / 101 (3.96) 11 / 103 (10.68)

[0300] Adjacent 4 / 101 (3.96) 8 / 103 (7.77) Non- adjacent 0 / 101 (0.00) 4 / 103 (3.88) Fractures Total 2 / 93 (2.15) 9 / 94 (9.57)

[0301] during first 3 Adjacent 2 / 93 (2.15) 5 / 94 (5.32)

[0302] months Non- adjacent 0 / 93 (0.00) 4 / 94 (4.26)

[0303]

Claims

Claims1. A poly(methyl methacrylate) (PMMA)-based bone cement for the use in a method for reducing the occurrence of vertebral fractures following vertebral augmentation therapy, characterized by injecting said bone cement into at least one vertebra of a subject.

2. The bone cement for the use according to claim 1 , wherein the at least one vertebra is osteopenic or osteoporotic.

3. The bone cement for the use of claim 1 , wherein at least one vertebra exhibits an osteopenic or osteoporotic bone structure.

4. The bone cement for the use according to claim 1 , wherein the subject suffers from osteopenia or osteoporosis.

5. The bone cement for the use according to claim 1 , wherein the at least one vertebra is fractured due to low impact trauma.

6. The bone cement for the use according to any of the preceding claims, wherein the at least one vertebra has a stable fracture.

7. The bone cement for the use according to any one of the preceding claims, wherein the subject has a bone density dual-energy x-ray absorptiometry (DEXA) test T-score below -1 , such as below -2.5.

8. The bone cement for the use according to any of the preceding claims, wherein the subject exhibits a pain intensity of at least 40 mm on a Visual Analogue Scale (VAS) prior to vertebral augmentation therapy.

9. The bone cement for the use according to any of the preceding claims, wherein the subject exhibits a pain intensity of at least 4 on a Numeric Pain Rating Scale (NPRS) prior to vertebral augmentation therapy.

10. The bone cement for the use according to claim 1 , wherein the subject suffers from multiple myeloma and / or hemangioma.

11. The bone cement for the use according to any one of the preceding claims , wherein the subject is a human male or female.

12. The bone cement for the use according to any one of the preceding claims, wherein the subject has vertebral augmentation therapy performed on one or more vertebrae selected from T5 to L5.

13. The method according to claim 1 , wherein the subject is at least 30 years, such as at least 40 years, such as at least 50 years, such as at least 60 years, such as at least 70 years, such as at least 80 years.

14. The bone cement for the use according to any one of the preceding claims, wherein the PMMA-based bone cement comprises a liquid component and a powder component, wherein the liquid component comprises a liquid cement component and a liquid softener.

15. The bone cement for the use according to claim 14, wherein the liquid cement component comprises methyl methacrylate (MMA), benzenamine, N,N,4- trimethyl and 1 ,4-dihydoroxy benzene.

16. The bone cement for the use according to claim 14, wherein the liquid cement component comprises MMA, N,N-dimethyl-p-toluidine (DMPT) and hydroquinone.

17. The bone cement for the use according to claim 14, wherein the powder component comprises PMMA, a radiopacifier, dibenzoyl peroxide and optionally a copolymer, such as (poly)styrene.

18. The bone cement for the use according to claim 14, wherein the powder component comprises PMMA, zirconium dioxide, dibenzoyl peroxide and optionally a copolymer, such as (poly)styrene.

19. The bone cement for the use according to claim 14, wherein the powder component comprises PMMA, barium sulfate, dibenzoyl peroxide and optionally a copolymer, such as (poly)styrene.

20. The bone cement for the use according to any one of claims 14 to 19, wherein the liquid softener is linoleic acid.

21. The bone cement for the use according to any one of claims 14 to 19, wherein the liquid softener is linoleic acid, ricinoleic acid, oleic acid, methyl linoleate, castor oil, linseed oil, and / or tung oil, preferably linoleic acid.

22. The bone cement for the use according to claim 14, wherein the liquid cement component comprises 90-99.9% (v / v) MMA, 0.1-5% (v / v) benzenamine, N,N,4- trimethyl and 30-85 ppm 1 ,4-dihydoroxybenzene.

23. The bone cement for the use according to claim 14, wherein the liquid cement component comprises 90-99.9% (v / v) MMA, 0.1-5% (v / v) benzenamine, N,N,4- trimethyl and 10-100 ppm 1 ,4-dihydoroxybenzene.

24. The bone cement for the use according to claim 14, wherein the liquid cement component comprises 90-99.9% (v / v) MMA, 0.1-5% (v / v) benzenamine, N,N,4- trimethyl and 25-75 ppm methyl ether of hydroquinone (MeHQ).

25. The bone cement for the use according to claim 14, wherein the powder component comprises 50-60% (w / w) PMMA, 40-55% (w / w) zirconium dioxide and 0.5-1.5% (w / w) (di)benzoyl peroxide.

26. The bone cement for the use according to claim 14, wherein the powder component comprises 60-80% (w / w) PMMA, 20-40% (w / w) barium sulfate and 0.5-2.5% (w / w) (di)benzoyl peroxide.

27. The bone cement for the use according to claim 14, wherein the powder component comprises 15-25% (w / w) PMMA, 40-55% (w / w) zirconium dioxide and 0.3-1.0% (w / w) (di)benzoyl peroxide.

28. The bone cement for the use according to claim 14, wherein the liquid softener constitutes 1-20% (v / v) of the liquid component, such as 1-5% (v / v), such as 1- 10% (v / v), such as 5-10% (v / v), such as 10-15% (v / v), such as 10-20% (v / v), such as 12-20% (v / v), such as 15-20% (v / v).

29. The bone cement for the use according to claim 14, wherein the liquid softener constitutes 1-25% (v / v) of the liquid component, such as between 5-20% (v / v), such as 8-16%.

30. The bone cement for the use according to claim 14, wherein the PMMA-based bone cement comprises 1-10 % (v / w) liquid softener, such as 2-6 % (v / w).

31. The bone cement for the use according to claim 14, wherein the liquid cement component comprises between 95-99,6% (v / v) methacrylic acid methyl ester, 0,4-5% (v / v) benzenamine, N,N,4-trimethyl and 25-100 ppm 1,4- dihydoroxybenzene.

32. The bone cement for the use according to claim 14, wherein the powder component comprises 45-65% (w / w) PMMA, 35-55% (w / w) zirconium dioxide and 0,4-1 ,2% (w / w) (di)benzoyl peroxide.

33. The bone cement for the use according to claim 14, wherein the powder component comprises 60-80% (w / w) PMMA, 20-40% (w / w) barium sulfate and 0,4-1 ,2%(w / w) (di)benzoyl peroxide.

34. The bone cement for the use according to claim 14, wherein the liquid cement component comprises 98.6% (v / v) methacrylic acid methyl ester, 1.4% (v / v) benzenamine, N,N,4-trimethyl and 50 ppm 1 ,4-dihydoroxybenzene.

35. The bone cement for the use according to claim 14, wherein the powder component comprises 54.2% (w / w) PMMA, 45% (w / w) zirconium dioxide and 0.8% (w / w) (di)benzoyl peroxide.

36. The bone cement for the use according to claim 14, wherein the powder component comprises 69.2% (w / w) PMMA, 30% (w / w) barium sulfate and 0.8% (w / w) (di)benzoyl peroxide.

37. The bone cement for the use according to claim 14, wherein the PMMA based bone cement comprises 1-8% (v / w) liquid softener, such as 2-5% (v / w).

38. The bone cement for the use according to claim 14, wherein a fraction of the PMMA in the powder component is partially pre-polymerized.

39. The bone cement for the use according to claim 14, wherein the liquid cement component and the powder component of the PMMA-based bone cement comprising a bone cement softener are present in a ratio between 1 :1.5 to 1 :3.

40. The bone cement for the use according to claim 14, wherein the liquid cement component and the powder component of the PMMA based bone cement comprising a bone cement softener are present in a 1 :2.3 ratio.

41. The bone cement for the use according to claim 14, wherein the final comsposition comprises 35-50% (w / w) polymer, selected from PMMA or MMA- co-styrene, 15-35% (w / w) radiopacifier, selected from barium sulfate or zirconium dioxide, 20-35% (w / w) MMA, 0.25-2.0% (w / w) benzoyl peroxide, 0.1-0.5% (w / w) benzenamine, N,N,4-trimethyl, 0.3-6.0% (w / w) bone cement softener, such as linoleic acid, and 3-30 ppm of an inhibitor selected from 1 ,4- dihydroxybenzene or 4-methoxyphenol.

42. The bone cement for the use according to any one of the preceding claims, wherein the PMMA based bone cement comprising a bone cement softener is a low-modulus bone cement.

43. The bone cement for the use according to any one of the preceding claims, wherein the PMMA based bone cement comprising a bone cement softener has an elastic modulus ex. vivo below 2000 MPa, such as below 1500 MPa, preferably below 1100 MPa, even more preferably below 1000 MPa, even more preferably below 800 MPa.

44. The bone cement for the use according to any one of the preceding claims, wherein the bone cement has a setting temperature below 40°C.

45. The bone cement for the use according to any one of the preceding claims, wherein the bone cement has a compression strength of 28.3 ± 5.1 MPa 24 hours after mixing.

46. The bone cement for the use according to any one of the preceding claims, wherein the occurrence of post-treatment adjacent vertebral fractures is reduced.

47. The bone cement for the use according to any one of the preceding claims, wherein the occurrence of post-treatment non-adjacent vertebral fractures is reduced.

48. The bone cement for the use according to any one of the preceding claims, wherein the occurrence of post-treatment vertebral re-fractures is reduced.

49. The bone cement for the use according to any one of the preceding claims, wherein post-treatment adjacent vertebral fractures are reduced by at least 60% after up to 3 months after vertebral augmentation therapy.

50. The bone cement for the use according to any one of the preceding claims, wherein adjacent post-treatment vertebral fractures are reduced by at least 40% after up to 3 months after vertebral augmentation therapy.

51. The bone cement for the use according to any one of the preceding claims, wherein post-treatment adjacent vertebral fractures are reduced by at least 20% after up to 3 months after vertebral augmentation therapy.

52. The bone cement for the use according to any one of the preceding claims, wherein post-treatment non-adjacent vertebral fractures are reduced by up to 100 %.

53. The bone cement for the use according to any one of the preceding claims, wherein less than 20% of all subjects having undergone vertebral augmentation therapy experience adjacent and non-adjacent fractures within 3 months after vertebral augmentation therapy.

54. The bone cement for the use according to any one of the preceding claims, wherein less than 10% of all subjects having undergone vertebral augmentation therapy experience adjacent and non-adjacent fractures within 3 months after vertebral augmentation therapy.

55. The bone cement for the use according to any one of the preceding claims, wherein less than 5% of all subjects having undergone vertebral augmentation therapy experience adjacent and non-adjacent fractures within 3 months after vertebral augmentation therapy.

56. The bone cement for the use according to any one of the preceding claims, wherein less than 2% of all subjects having undergone vertebral augmentation therapy experience adjacent and non-adjacent fractures within 3 months after vertebral augmentation therapy.

57. The bone cement for the use according to any one of the preceding claims, wherein the vertebral augmentation therapy involves kyphoplasty, vertebroplasty or implant supported vertebral augmentation.

58. The bone cement for the use according to any one of the preceding claims, wherein the vertebral augmentation therapy involves injecting 1-6 ml PMMA based bone cement, such as 2-4 ml, such as preferably 3 ml.

59. The bone cement for the use according to any one of the preceding claims, wherein the vertebral augmentation therapy involves injecting 1-10 ml PMMA based bone cement, such as 3-8 ml, such as 4-6 ml, such as preferably 5 ml.

60. The bone cement for the use according to any one of the preceding claims, wherein said PMMA based bone cement has an injection time window of up to 15 minutes, such as up to 17 minutes, such as up to 18 minutes, such as up to 19 minutes, such as up to 20 minutes, such as up to 25 minutes.

61. The bone cement for the use according to any one of the preceding claims, wherein said PMMA based bone cement has an injection time window of up to 25 minutes, such as up to 20 minutes, such as up to 19 minutes, such as up to 18 minutes, such as upto 17 minutes, such as upto 15 minutes.

62. The bone cement for the use according to any one of the preceding claims, wherein said vertebral augmentation therapy maintains vertebral height.

63. The bone cement for the use according to any one of the preceding claims, wherein said vertebral augmentation therapy maintains the vertebral height for up to 12 months.

64. The bone cement for the use according to any one of the preceding claims, wherein said vertebral augmentation therapy maintains the vertebral height for up to 24 months.

65. The bone cement for the use according to any one of the preceding claims, wherein lower back (T5 to L5) pain in a subject is below 100 on the Visual Analog Scale (VAS) such as below 50, such as below 30, such as below 20, such as preferably below 10, directly after vertebral augmentation therapy.

66. The bone cement for the use according to any one of the preceding claims, wherein lower back (T5 to L5) pain in a subject is below 100 on the VAS scale such as below 50, such as below 30, such as below 20, such as preferably below 10, 5 days after vertebral augmentation therapy.

67. The bone cement for the use according to any one of the preceding claims, wherein lower back (T5 to L5) pain in a subject is below 100 on the VAS scale such as below 50, such as below 30, such as below 20, such as preferably below 10, 3 months after vertebral augmentation therapy.

68. The bone cement for the use according to any one of the preceding claims, wherein lower back (T5 to L5) pain in a subject is below 100 on the VAS scale such as below 50, such as below 30, such as below 20, such as preferably below 10, 1 year after vertebral augmentation therapy.

69. The bone cement for the use according to any one of the preceding claims, wherein lower back (T5 to L5) pain in a subject is below 100 on the VAS scale such as below 50, such as below 30, such as below 20, such as preferably below 10, 2 years after vertebral augmentation therapy.

70. The bone cement for the use according to any one of the preceding claims, wherein the lower back pain (T5 to L5) in a subject is reduced to below 10 on the Numeric Pain Rating Scale (NPRS) scale, such as below 5, such as below 4, such as below 3, such as preferably below 2, directly after vertebral augmentation therapy.

71. The bone cement for the use according to any one of the preceding claims, wherein the lower back pain (T5 to L5) in a subject is reduced to below 10 on the NPRS scale, such as below 5, such as below 4, such as below 3, such as preferably below 2, 5 days after vertebral augmentation therapy.

72. The bone cement for the use according to any one of the preceding claims, wherein the lower back pain (T5 to L5) in a subject is reduced to below 10 on the NPRS scale, such as below 5, such as below 4, such as below 3, such as preferably below 2, 3 months after vertebral augmentation therapy.

73. The bone cement for the use according to any one of the preceding claims, wherein the lower back pain (T5 to L5) in a subject is reduced to below 10 onthe NPRS scale, such as below 5, such as below 4, such as below 3, such as preferably below 2, 1 year after vertebral augmentation therapy.

74. The bone cement for the use according to any one of the preceding claims, wherein the lower back pain (T5 to L5) in a subject is reduced to below 10 on the NPRS scale, such as below 5, such as below 4, such as below 3, such as preferably below 2, 2 years after vertebral augmentation therapy.

75. The bone cement for the use according to any one of the preceding claims, wherein the Oswestry Disability Index (ODI) in a subject is below 50, such as below 40, such as below 30, such as below 20, such as preferably below 10, 5 days after vertebral augmentation therapy.

76. The bone cement for the use according to any one of the preceding claims, wherein the ODI in a subject is below 50, such as below 40, such as below 30, such as below 20, such as preferably below 10, 3 months after vertebral augmentation therapy.

77. The bone cement for the use according to any one of the preceding claims, wherein the ODI in a subject is below 50, such as below 40, such as below 30, such as below 20, such as preferably below 10, 1 year after vertebral augmentation therapy.

78. The bone cement for the use according to any one of the preceding claims, wherein the ODI in a subject is below 50, such as below 40, such as below 30, such as below 20, such as preferably below 10, 2 years after vertebral augmentation therapy.

79. The bone cement for the use according to any one of the preceding claims, wherein the Quality of Life assessed by the Short Form 12 Physical Component Summary (SF12 PCS) in a subject is above 50, such as above 60, such as above 70, such as above 80, such as preferably above 90, 5 days after vertebral augmentation therapy.

80. The bone cement for the use according to any one of the preceding claims, wherein the Quality of Life assessed by the Short Form 12 Physical Component Summary (SF12 PCS) in a subject is above 50, such as above 40, such asabove 30, such as above 20, such as preferably above 10, 3 months after vertebral augmentation therapy.

81. The bone cement for the use according to any one of the preceding claims, wherein the Quality of Life assessed by the Short Form 12 Physical Component Summary (SF12 PCS) in a subject is above 50, such as above 40, such as above 30, such as above 20, such as preferably above 10, 1 year after vertebral augmentation therapy.

82. The bone cement for the use according to any one of the preceding claims, wherein the Quality of Life assessed by the Short Form 12 Physical Component Summary (SF12 PCS) in a subject is above 50, such as above 40, such as above 30, such as above, 20, such as preferably above 10, 2 years after vertebral augmentation therapy.

83. A method of performing vertebral augmentation therapy with a reduced risk of new vertebral fractures, comprising injecting at least one vertebra of a subject in need of vertebral augmentation therapy with a PMMA-based bone cement comprising a bone cement softener, thereby reducing the risk of new vertebral fractures.

84. A method of protecting vertebrae against new vertebral fractures in a subject undergoing vertebral augmentation therapy comprising injecting at least one vertebra with a PMMA-based bone cement comprising a bone cement softener into at least one vertebra.

85. A method of protecting the spine against new vertebral fractures comprising injecting at least one vertebra in need of vertebral augmentation therapy with a PMMA-based bone cement comprising a bone cement softener.

86. A method of performing vertebral augmentation therapy, comprising injecting at least one vertebra of a subject in need of vertebral augmentation therapy with 4-8 ml of a PMMA based bone cement comprising a bone cement softener.

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