CN101663043A - Methods and compositions for promoting and maintaining bone growth - Google Patents

Abstract

A method of augmenting bone in a subject in need thereof, the method comprising installing a sufficient amount of biocompatible material inside a bone in the subject to form a scaffold inside the bone, wherein the The scaffold serves as a vehicle for the formation of new bone within the bone, and a sufficient amount of at least one bone-augmenting agent is administered to the subject to increase the blood concentration of at least one anabolic agent in the subject. The method can further comprise administering to the subject at least one antiresorptive agent in an amount sufficient to substantially prevent resorption of new bone growth. In another embodiment, the method may further comprise the step of mechanically inducing an increase in osteoblast activity in the subject, wherein the increase in the blood concentration of the anabolic agent and the increase in osteoblast activity are at least within overlap in time.

Description

Methods and compositions for promoting and maintaining bone growth

technical field

The present invention generally relates to methods and compositions for promoting and maintaining bone growth in a subject. More specifically, the present invention includes inducing rapid bone formation and thereafter maintaining such formation at locations such as fracture sites, in areas of reduced bone density in bones, and/or in regions such as portions of long bones lacking cancellous bone structure new bone, while promoting the growth of additional bone at any such location by, for example, providing an internal framework or scaffold upon which the newly created bone can anchor and grow. Antiresorptive agents may optionally be administered for the purpose of reducing resorption of newly formed bone over time.

Background technique

The bones of the skeleton are not all completely solid. The outer bone, the cortical bone, is essentially solid with only a few small (Hafferian) tubes. However, inward from the cortical bone is spongy bone called cancellous bone (or trabecular bone). Cancellous bone consists of a cellular network of trabecular bone that defines numerous spaces or cavities filled with fluid marrow, stem cells, and some fat cells. Within these bone marrow cavities reside a variety of highly specialized cells that help degrade existing bone (called osteoclasts) and corresponding cells that produce new bone (called osteoblasts) to replace degraded cells or possibly otherwise Cells lost due to factors such as injury or disease.

As noted above, the physical structure of bones can be compromised for a variety of reasons, including injury and disease. One of the most common bone diseases is osteoporosis, which is characterized by low bone mass and structural deterioration of bone tissue, resulting in weak bones and greater susceptibility to fractures, especially in the hips, spine and wrists. Osteoporosis develops in an imbalance in which the rate of bone resorption exceeds the rate of bone formation. This is partly due to the fact that it can take six months for osteoblasts to rebuild the amount of bone that osteoclasts have destroyed in three days. For example, the average woman with osteoporosis has lost thirty percent of her bone mass by the age of fifty-five.

Osteoporosis accelerates dramatically during menopause and is the third leading cause of death in women over seventy. The disease afflicts men as well, with men accounting for 20 percent of all osteoporosis victims. By the age of seventy-five, approximately 90 percent of all women and 33 percent of all men will suffer from osteoporosis. The disease causes 1.5 million fractures each year and costs the United States more than $18 billion in annual health care costs. For people over the age of 50, one in two women and one in eight men will experience an osteoporosis-related fracture during their lifetime. Among people who suffer a hip fracture, one in five will not live past a year. Currently, less than 10 percent of patients treat osteoporosis with prescription medications.

Such prescription drugs usually include at least one bone augmentation agent. As used herein, the term "bone-expanding agent" includes, but is not limited to, bone anabolic agents, and agents that cause increased blood levels of endogenous bone anabolic agents to be produced in a subject. Bone augmenting agents such as bone anabolic agents are well known in the art. Bone anabolic agents typically include (but are not limited to) parathyroid hormone and various parathyroid hormone fragments, whether in amidated or free acid form, as well as PTHrP and its analogs, prostaglandin E-2, bone morphogenetic protein, IGF-I, growth hormone, fibroblast growth factor TGF and others. On the other hand, agents that cause increased expression of endogenous bone anabolic agents include, but are also not limited to, calcilytic agents and anti-sclerostin antibodies. Calcilytic agents usually, but not necessarily, include agents that limit the binding of calcium to its receptors, thereby triggering the release of endogenous parathyroid hormone. Examples of these materials are given in US Patents 6,362,231, 6,395,919, 6,432,656, and 6,521,667, the contents of which are expressly incorporated herein by reference.

However, relying on the administration of bone-augmenting agents, such as those described above, for purposes such as increasing bone density, often involves prolonged treatment regimens with attendant patient compliance issues. In addition, this treatment produces a systemic effect on the entire skeletal system, so it is not and cannot be "targeted" to have an effect in one or more specific bones.

Therefore, in order to provide a faster and more targeted method of inducing bone formation and helping to maintain the retention of new bone growth so produced in a subject suffering from, for example, decreased bone mass, several aspects of the present invention The two co-inventors have developed a method of promoting bone formation and maintenance that overcomes the above-mentioned deficiencies of the prior art. The method comprises the steps of mechanically inducing increased osteoblast activity in one or more "targeted" bones of a subject in need of additional bone growth, and increasing at least one bone anabolic agent in the subject The blood level steps, wherein the above steps can be performed in any order, but wherein they are performed in close enough time that the increased concentration of the bone anabolic agent and the mechanically induced increase in osteoblast activity overlap at least in part. The above methods are described, for example, in US Patent Application Serial No. 11/128,095, filed May 11, 2005, and US Continuation-in-Part Application Serial No. 11/267,987, filed November 7, 2005. The contents of both applications are incorporated herein by reference. As mentioned above, this method allows specific targeting of specific bones for effects such as repair, reinforcement, reshaping and/or remodeling.

Although it has been found that the above approach is particularly effective at growing and maintaining new bone when the area targeted for this additional bone growth is provided with a sufficient amount of cancellous bone to act as a scaffold to support the new growth, it is now clear that New bone produced by the action of a bone anabolic agent alone, whether such agent is endogenous or not, may not be ideal for bone replacement in areas lacking sufficient cancellous bone to act as a scaffold. In addition, the use of PTH and other anabolic agents may not be sufficient to fill gaps in trabecular bone created by perforation due to increased bone resorption. Over time, some of the bone created by bone augmenting agents, including but not limited to anabolic agents, may be lost through this resorption in those areas lacking bone scaffolding as described above. Previous attempts to prevent or minimize such absorption have involved the administration of anti-resorptive agents well known in the art. These agents include, but are not limited to, calcitonins including, for example, human calcitonin, salmon calcitonin, eel calcitonin, elkatonin, porcine calcitonin, chicken calcitonin, SERMS (select estrogen receptor modulators), bisphosphonates, strontium ranelate, and combinations thereof. This imparts an antiresorptive agent that protects the newly formed bone. However, some or all of the new bone formed during the initial growth "burst" promoted by the presence of the anabolic agent may still be resorbed by the subject. Consequently, the effects of new bone, such as increased bone strength and/or support, will be diminished.

However, the present inventors have discovered that the addition of a biocompatible matrix forming material in these specific areas will prevent new targeted bone loss as it will act as a scaffold for additional bone growth. Additionally, it has been found that the installation of such a biocompatible matrix allows for better bone synthesis in areas such as the long bone diaphysis such as the humeral diaphysis.

For purposes of illustration, one particular location where bone thinning and consequent bone damage problems, including fractures, occur is in the vertebrae of the spine. Vertebroplasty and kyphoplasty, which are currently commonly used in the United States, are surgeries that augment the vertebrae and also treat pain caused by vertebral compression fractures. Both procedures use X-ray guidance and a transpedicular or parapedicular technique to access the vertebral body for injection of fluid cement therein. The cement is then cured to augment the weakened and painful vertebrae. The simplest surgical procedure is vertebroplasty. This technique is discussed, for example, in US Patent 6,273,916, the contents of which are incorporated herein by reference. A more recent procedure that has become more common is kyphoplasty, which involves inflating a balloon to restore height while bone cement is injected into the cavity created by the balloon.

A very popular bone cement used for these surgical procedures is polymethyl methacrylate ("PMMA"). The use of PMMA has been described in several specialized journal articles, including: (a) "Is Percutaneous Vertebroplasty without Pretreatment Venography Safe? Evaluation of 205 Consecutive Procedures (Is Percutaneous Vertebroplasty without Pretreatment Venography Safe? 205 Evaluation of Serial Surgical Procedures), Cristiana Vasconcelos, Philippe Gailloud, Norman J. Beauchamp, Donald V. Heck, and Kieran J. Murphy, AJNR Am J Neuroradiol 23:913-917, June/July 2002 (“Vasconcelos” ); (b) "Bone Cements: Review of Their Physiochemical and Biochemical Properties in Percutaneous Vertebroplasty" by Matthew J.Provenzano, Kieran P.J.Murphy and Lee H. Riley III, AJNR Am J Neuroradiol 25:1286-1290, August 2004 ("Provenzano"); (c) "The Chemistry of Acrylic Bone Cements and Implications for Clinical Usein Image-Guided Therapy" Chemical properties and implications for clinical application in image-guided therapy)", David A. Nussbaum, M S, Philippe Gailloud, MD, and Kieran Murphy, MD., J Vase Interv Radiol 2004; 15 Page 1. ("Nussbaum") . The contents of each of these articles are incorporated herein by reference.

PMMA is an acrylic bone cement. It is non-sticky and does not bond to bone over time, yet it is very strong. As an analogy, PMMA acts as the reinforcing steel in cement used in the construction of buildings. However, the use of PMMA does have significant disadvantages, as PMMA is known to eliminate or reduce the forces that maintain bone density by displacing the action of its nearby trabecular bone structure, thereby eliminating or reducing electrical charges that contribute to bone development.

Furthermore, the monomer liquid used to dissolve the PMMA powder can be toxic, which has been linked to complications such as death and cardiac arrest (see Nussbaum article). Additionally, the high compressive strength of PMMA can cause fractures of adjacent vertebral bodies by exerting high non-compliant forces on adjacent vertebrae as the vertebral bodies become too stiff due to injection of PMMA. These adjacent fractures occur eight to ten percent of the time.

Promising alternatives to PMMA are bioactive bone cements or biocompatible polymers. Bioactive bone cements avoid some of the difficulties encountered with the use of PMMA. For example, bioactive bone cements may be of lower strength than PMMA, resulting in less vertebral body stiffness when they are injected. However, there are several problems inherent in their use, for example, in vertebral augmentation. For example, bioactive bone cements are very difficult to inject, they lack natural radio density, and they don't always bond well over months or even years. In addition, some bioactive bone cements require hours to cure and become safe. More importantly, there have been cases of death with the use of some of these cements, which may be related to the pH of the cement injected, or to leakage of calcium into the circulation leading to disseminated coagulation. However, little is currently known about how bioactive bone cements are used in vertebral augmentation surgical procedures.

A bioactive bone cement that can be used for vertebral augmentation is calcium phosphate. Calcium phosphate cement consists of a powder and a liquid solution in which the powder is dissolved. They are widely used in hip, spine and wrist surgery and also in cranial restriction. There are two different classes of calcium phosphate cements. One type undergoes an exothermic reaction, while the other type undergoes an endothermic reaction. One class belongs to the class known as bruschite cements. The other belongs to the category of precursors that eventually form hydroxyapatite, bone. When calcium phosphate powder is mixed with an aqueous solution, a paste is formed that sets within minutes to hours. As such, they tend to be poorly injectable and have poor visibility under X-ray guidance, making them difficult to use in vertebral augmentation procedures. Furthermore, when they are delivered into bone, they are acted upon by osteoblasts and osteoclasts in the residual trabecular bone structure. If there is no residual trabecular bone structure, the peripheral cement may bind to the endosteal surface of the bone, but the cement located in the vertebral mass may remain in its unchanged form, i.e., low in tensile and compressive strength, Brittle ceramic materials with potential long-term negative consequences.

In view of the above-mentioned deficiencies of the prior art, there is a long-felt unmet need for those skilled in the art to induce bone formation in bones lacking a bony scaffold of trabecular bone and to enhance the degree of maintenance of the new bone so produced faster and more efficient method. These desired functions are well accomplished by the present invention in the manner described hereinafter.

Contents of the invention

It is therefore an object of the present invention to provide novel and non-obvious methods of inducing relatively rapid targeted bone growth in all desired locations, while maintaining and amplifying the new bone growth thus obtained.

In general, and as described in further detail below, the present invention provides a method for introducing a biocompatible material formed from a bioactive cement or other matrix forming material into the interior of a bone to induce new bone growth in the area , thereby incorporating cement or other matrix material into the existing bone architecture along with the new bone. In one embodiment of the invention, stromal cell removal, such as by flushing, acts as a stimulator of targeted new bone growth, wherein bone augmentation compositions such as bone anabolic agents prolong this response, and wherein matrix forming material fills the The void in the interior of the bone lacks trabecular bone, and acts as a scaffold for new bone growth in areas lacking a sufficient amount of such trabecular bone, as well as in areas lacking it completely. For example, a cyclic treatment regimen of bone marrow flushing-administration of anabolic agents-installation of a biocompatible matrix in the interior of the bone-antiresorptive therapy is contemplated according to the invention.

The present invention thus provides, in one embodiment, a method of augmenting bone in a subject in need thereof, wherein the method comprises installing a sufficient amount of biocompatible material in the interior of the bone in the subject to allow for bone augmentation in the subject. internally forming a scaffold that acts as a vehicle for new bone formation in the interior of the bone; and administering to the subject a sufficient amount of at least one bone augmenting agent to increase the blood flow of the at least one anabolic agent in the subject concentration.

In another embodiment, the present invention provides a method of expanding bone in a subject in need thereof, wherein the method comprises mechanically inducing an increase in osteoblast activity in the subject; increasing the interior of the bone in the subject that has been induced, installing a sufficient amount of biocompatible material to form a scaffold within the bone that acts as a vehicle for new bone formation in the interior of the bone; and administering to the subject A sufficient amount of the at least one bone-augmenting agent for the subject to increase the blood concentration of the at least one bone anabolic agent in the subject, wherein the increase in the blood concentration of the bone anabolic agent in the subject is associated with osteogenesis The increases in cellular activity at least partially overlap in time.

In yet another embodiment, the present invention is directed to a kit for promoting and maintaining bone growth in the interior of bones lacking sufficient trabecular scaffolding to substantially prevent resorption of new bone formed therein . The kit includes at least one container having therein at least one biocompatible material adapted to form an additional amount of scaffolding within the bone; and at least one container having therein a bone augmentation agent.

In yet another embodiment, the present invention is directed to a kit for promoting and maintaining bone growth in the interior of bones lacking sufficient trabecular scaffolding to substantially prevent resorption of new bone formed therein . The kit comprises at least one container having at least one biocompatible material suitable for forming an additional amount of scaffolding inside the bone; at least one container having a bone augmentation agent therein; A device that mechanically alters the contents of the marrow cavity in a bone.

Description of drawings

Figure 1A is a cross-section of the midsection of a rat femur after 21 and 84 days of treatment, respectively. The following groups were included: (a) control group - no bone marrow depletion ("BMX") or anabolic agent; (b) BMX - bone marrow depletion only; and (c) BMX+PTH - bone marrow depletion plus treatment with PTH 1-34NH ₂ Treatments for 21 or 84 days. Additionally, rats were injected with calcein, a fluorescent dye, 9, 8, 2 and 1 day before sacrifice. Calcein is incorporated into bone and acts as a measure of bone growth and mineralization.

Figure 1B depicts the results obtained from these same groups of animals using an imaging technique known as Micro-CT. This technique provides high resolution analysis of the femoral shaft medullary cavity of control, BMX and BMX+PTH 1-34 _NH2 rats treated with PBS (buffer) or PTH for 21 or 84 days;

Figure 2 is a flow diagram depicting a method of augmenting bone according to one embodiment of the present invention; the procedure requires the administration of a biocompatible matrix material, plus the administration of a bone augmentation agent such as a bone anabolic agent, said biocompatible The matrix material can be, but need not be, a biocompatible bone cement.

FIG. 3 shows an axial view of a vertebra with an osteoporotic fracture undergoing administration of a biocompatible matrix material, such as bioactive bone cement, to perform one of the steps shown in FIG. 2 . A biocompatible material is injected into spaces devoid of cancellous bone to provide a scaffold that aids in lasting bone formation.

4 is a schematic illustration of administering a bone augmenting agent, such as a bone anabolic agent, to perform one of the steps shown in FIG. 2 . The biocompatible matrix can be accompanied or mixed with an anabolic agent. Additionally, the anabolic agent may alternatively be administered systemically to a subject.

5 is a schematic illustration of an axial view of an osteoporotic vertebra undergoing administration of a biocompatible matrix slurry to perform one of the steps shown in FIG. 2, according to another embodiment of the present invention. In this case, there is residual cancellous bone that will respond to the combined action of mechanically inducing an increase in osteoblast activity, for example by flushing at least part of the medullary cavity, on the one hand, and administration of anabolic agents, on the other hand, But for areas lacking trabecular integrity, the addition of a biocompatible material will fill the pores and provide the necessary framework for continued new bone growth.

Figure 6A shows the extent of sustained bone growth achieved after 84 days of administration of a biocompatible material, in this case Cementek (Cementek LV, from the reaction between acidic and basic calcium phosphate in the presence of aqueous solution Prepared non-stoichiometric hydroxyapatite, Teknimid, 65500 VIV en Biggore, France) or Pepgen-15 (high purity inorganic (anorganic) bovine graft material, radiopaque, peptide enhanced to mimic autogenous bone, Dentsply Friadent CeraMedLakewood, CO ). All samples were taken from femurs that underwent BMX. Groups included: BMX, followed by 84 days of anabolic or PBS (buffer) treatment, shown in the first row; 84 days with or without PTH treatment;

Figure 6B depicts the results obtained from the same groups of animals reported in Figure 6A using Micro-CT imaging. This imaging technique provides high-resolution analysis of the medullary cavity of the femoral shaft treated with BMX+PBS or PBX+PTH, in contrast to injected biocompatible materials (Cementek or Pepgen -15) Femurs into the medullary cavity were compared.

Figures 7A and 7B show the effect attributable to administration of the antiresorptive agent alendronic acid in maintaining bone tissue formed according to the methods of the present invention. The following treatment regimens were included: (a) BMX+PTH 1-34NH ₂ for 21 days + PBS (buffer) for days 22-84; (b) BMX+PTH 1-34NH ₂ for 21 days + calcitonin for days 22-84 days; (c) BMX+PTH 1-34NH ₂ 21 days + alendronic acid days 22-84; and (d) BMX+PTH 1-34NH ₂ days 1-84.

Figure 7B depicts the results obtained from the same groups of animals reported in Figure 7A using the Micro-CT imaging technique that provides high resolution analysis of the medullary cavity of the femoral shaft.

Detailed ways

The invention will now be described, by way of example only, with reference to certain embodiments and drawings. As noted above in the discussion of the background to the invention, the inventors have determined that in areas lacking cancellous bone, new formation through the action of bone-expanding agents such as bone anabolic agents (e.g., parathyroid hormone) Bone, which may not be permanent in nature, may actually be at least partially resorbed if anabolic therapy (alone) is continuously applied. To solve this problem, the present invention describes two different methods to maintain new bone in the medullary cavity lacking this cancellous bone "scaffold", namely, the cycling of strong antiresorptive agents such as bisphosphonates. ) or the inclusion of one or more biocompatible materials such as, but not limited to, biocompatible bone cement, which act as a scaffold to support new bone growth and facilitate its maintenance.

For the convenience of explaining the present invention, the material used to form a scaffold in the targeted bone to promote bone growth according to the present invention is often referred to as "biocompatible material" and/or "bioactive material" hereinafter. This term is defined herein to include not only bone cements (including biocompatible bone cements), but also now known or later discovered alternative materials that provide the ability to form the desired scaffold inside the bone, such as polymers, gelatinous Glue and/or foam, calcium phosphate or hydroxyapatite slurry or suspension.

It is also understood that in areas with sufficient cancellous bone to provide scaffolding, mechanically induced increases in osteoblast activity, such as by bone marrow irrigation, combined with administration of bone-expanding agents such as bone anabolic agents, are sufficient to maintain anabolic New bone growth during agent treatment. However, in bones where the trabecular bone microarchitecture is deficient (see, e.g., FIGS. 1A and 1B ) or has been compromised and/or where many trabecular bones have been perforated, the addition of biocompatible Bone Marrow Flush and Anabolic Agent Treatment - Improves overall bone augmentation and maintenance. Even in the case of concomitant administration of, for example, bone anabolic agents and induction of increased osteoblast activity in bones targeted for this additional bone growth, osteogenesis was found in long bone diaphyses lacking cancellous bone architecture. Absorption, the induction technique is described, for example, in application serial numbers 11/128,095, filed May 11, 2005, and application serial numbers 11/267,987, filed November 7, 2005, both of which are incorporated herein by reference and into this application.

For example, as shown in Figure 1A, treatment with PTH for 21 days prolongs the period of bone formation following BMX and results in additional bone formation. At day 84, bone remodeling had occurred, resulting in the resorption of a substantial portion of the bone present at day 21 in the BMX and BMX+PTH groups. These results suggest that resorption occurs over time in areas of the bone that lack the cancellous bone network (ie, the scaffold).

Looking at Figure 1B, it can be noted that there is abundant BMX-induced newly formed bone in the medullary cavity at day 21, which was further expanded with PTH treatment for 21 days. In contrast, the medullary cavity of the midshaft of the BMX-treated femur from rats treated with PBS or PTH for 84 days was no longer undergoing bone formation and indeed no longer contained substantial bone. These results confirm the observations obtained with calcein labeling shown in Figure 1A.

Although, as noted above, bone resorption can be slowed and/or reduced by administering antiresorptive agents such as calcitonin and/or alendronic acid, for obvious reasons bone loss still needs to be removed if not completely eliminated. Losses are reduced to the extent possible, and this is achieved with the methods and compositions of the present invention applicable to long bones, hips, spines, and indeed any cancellous bone network lacking (or reduced). The present invention thus provides methods and compositions that achieve both: rapid and sustained targeted bone growth, and the desired reduction in the loss of new bone so generated due to factors such as resorption in specific targeted areas of bone.

In one embodiment, as shown at 100 in Figure 2, the present invention is directed to a method of augmenting bones in an individual, including but not limited to long bones such as femur and humerus as well as smaller bones such as vertebrae. The term "augmentation" as used herein refers to an increase in the amount and/or density of bone tissue contained in a bone, with a corresponding reduction or, if possible, complete prevention of the subsequent acceleration of newly formed bone tissue produced using the methods of the present invention absorb.

The above aspects are achieved with a method comprising administering in one step a bioactive material, such as bone cement, into the interior of the bone to be augmented. Biocompatible materials, including but not limited to bone cement, can be delivered in a radiographically controlled way or by open surgical application. Various biocompatible materials that are useful in the methods of the invention are described in more detail below.

The bioactive material binds to the trabecular bone structure in the interior of the "target" bone, forming a scaffold within it that acts as a scaffolding that facilitates the growth of additional bone at that location, so that in the desired area, such as where a fracture has occurred or For example, restoring normal bone functionality and strength to areas at risk of future fractures due to loss of bone density. Over time in the presence of anabolic agents, cement and newly formed bone integrate into the existing bone structure. This is advantageous because normal trabecular bone has complex weight distribution, compressive shear strength, and regenerative properties that cannot be reproduced with bone cement alone.

In the discussions herein, the methods exemplified by the invention are often performed by means of augmentation of the vertebrae. However, the present invention should not be construed as being limited to use with vertebrae only. That is, as noted above, other bones may also be augmented by the methods described herein, including but not limited to the hip bone, proximal femoral neck, distal radius, proximal humerus, calcaneus, one or more ribs, tibia and sacrum.

Referring first to Figure 3 provided in the present application, a vertebra is generally indicated at 50 . Vertebrae 50 having an osteoporotic fracture or spinal deformity exemplifies one type of bone and corresponding condition (ie, fracture) that may be treated by method 100 . Thus, to treat vertebrae 50 with method 100, step 110 is performed, which includes administering a bioactive material after flushing to remove stromal cells. In some cases, the introduction of a biocompatible material into the bone may serve as a method of removing stromal cells, but a preferred method involves an initial flush to effectively remove the stromal cell marrow.

In the case of a vertebra such as vertebra 50, the administration of the biocompatible material is typically performed with vertebroplasty or kyphoplasty. In FIG. 3 , cone 50 is shown undergoing vertebroplasty to achieve step 110 . The figure thus shows a vertebroplasty needle 54 inserted according to a transpedicular approach, the tip of the needle 54 being placed in a vertebral body 58 . Flushing and removal of stromal cells can be accomplished using the same needle, or a specially modified needle that provides a better method of stromal cell flushing and collection.

It should be understood that the performance of step 110 on vertebrae 50 may be accomplished using any currently known or future contemplated vertebroplasty technique, with appropriate or desired needles, image guidance schemes, and the like. The type of biocompatible material (eg, bone cement) 62 will affect these selections, and will also be selected as a means to complement the selection to achieve step 120 .

As yet another way of performing the method 100, the administration of the augmenting agent of the biocompatible material can be realized by injection into the vertebral body respectively. Thus, cement or other biocompatible matrix material can be injected into one pedicle of the vertebral body and bone augmentation agent injected into the other pedicle, or through an ipsilateral procedure. approach) injected through the same pedicle as the biocompatible material, or otherwise blended with it. Anabolic agents can also be administered systemically.

In the methods of the invention described herein, it is contemplated that the biocompatible material is in one embodiment of the invention at least one biocement, also referred to herein as a bioactive bone cement. Suitable biocompatible materials include, but are not limited to, calcium phosphate, calcium hydroxyapatite, calcium sulfate, calcium aluminate, bone morphogenetic protein, polymers, fibrinogen, synthetic fibrin, collagen gel, collagen plus Hydroxyapatite suspensions and their various combinations. Specific examples of such materials—provided for the purpose of illustrating (not limiting) the present invention only—include (a) Alpha-BSM bone substitute material, which comprises engineered (engineer) bone chemical composition and crystal structure Synthetic bioabsorbable bone substitute material, sold by ETEX Corporation, Cambridge MA; (b) Cortoss synthetic cortical bone, which contains three bifunctional pastes delivered as two mix-on-demand pastes Cross-linked resin, sold by Orthovita Corp., Malverne PA; (c) Cementek LV, which is a non-stoichiometric hydroxyapatite prepared from the reaction between acidic and basic calcium phosphate in the presence of aqueous solution, manufactured by Sold by Teknimid en Bigorre; (d) Pepgen P-15, a high-purity inorganic bovine graft material, radiopaque, peptide-enhanced to mimic autogenous bone, sold by Dentsply Friadent CereaMed Lakewood COP-P; (e) Norian SRS ( Bone Repair System), which is an injectable, moldable and biocompatible calcium phosphate that solidifies at body temperature into carbonate apatite, sold by Synthes, Inc. of West Chester, PA.

It may be desirable to select a combination of these materials where one or more cements provide, for example, short-term stability and/or pain relief, while the other provides long-term integration and new bone development. The choice of biomaterial will be site-specific. For example, the biocompatible material used to prevent hip fractures will be different than the biomaterial used to support vertebrae during vertebroplasty. Additionally, biocompatible materials will not be used off the shelf condition in most cases. That is, its formulation and/or physical state will be modified as needed for a particular application, for example by conversion into a suspension, foam or gel, and/or by modifying the concentration, size, and size of the solid particles that make up these materials , shape etc. are improved.

Enhanced bone cements can also be used in the present invention, including bone cements and augmentation agents. Examples of bone cements for such enhanced bone cements include Cementek and Cementek LV, while examples of expanders for these enhanced bone cements include, but are not limited to, insulin-related growth factor ("IGF"), rhPTH , GH, anabolic vitamin D analogs, activators of low-density lipoprotein receptor-related protein 5 (LRP5) or inhibitors of sclerostin binding to LRP5, nongenomic activators of estrogen signaling (ANGELS), bone Morphogenetic proteins, growth hormone releasing factor (GHRF), hepatocyte growth factor (HGF), calcitonin gene-related peptide (CGRP), parathyroid hormone-related peptide (PTHrP), transforming growth factor (TGF) and/or their The combination.

According to the present invention, the embodiments described herein additionally comprise a further step (ie performed in conjunction with the installation of the bioactive bone cement in the target bone) which involves administering the bone augmentation agent to the subject. It is contemplated that the bone augmentation agent will be administered to the subject daily for up to six months, for example. The augmenting agent, such as the bone anabolic composition, helps to: promote or otherwise enhance the placement of trabecular bone on the surface of the scaffold formed by the bone cement, at least as compared to the use of either the bone cement or the bone augmentation agent alone. growth, followed by a reduction in the extent of bone resorption. Bone augmentation agents may be administered in any suitable manner, including injection, intravenous ("IV"), oral ("PO"), transdermal, nasal, or rectal, and after the bone cement is installed inside the bone Any suitable time before, during or after.

As noted above, ie, according to routes of administration such as transdermal and nasal, the augmenting agent may be administered systemically, or directly at the site where the bone cement is introduced. The timing and method of administration of bone augmenting agents will be well known to those of ordinary skill in the art. That is, the steps in method 100 may be performed in an order different from that shown, or performed concurrently. The bone augmentation agent may be an anabolic agent as described above or any other agent that facilitates the incorporation of the injected cement. As noted above, it has been found that the combined effect of bone augmentation agents and that provided by bone cement contributes to a faster transition to bioactive bone than is typically achieved in low quality trabecular bone in patients with osteoporosis. The cement transforms into actual bone. In the absence of bone anabolic agents, bone cement will be resorbed, reducing its effectiveness. Some useful bone augmentation agents are exemplified below.

In one specific embodiment, such as that shown in FIG. 4 , a sufficient amount of one preferred bone anabolic agent, PTH[1-34]NH ₂ , is administered to patient 68, for example, through needle 72, to achieve and maintain a bone density in the subject. It has a pulsatile blood concentration of about 50 to about 350 pg/ml, preferably about 100 to about 200 pg/ml, most preferably about 150 pg/ml. In another embodiment, the blood concentration of PTH[1-34] _NH2 in the patient is increased to its preferred level no later than 7 days after performing step 110. Determining the appropriate dosage of PTH[1-34] _NH2 to achieve the desired blood level is understood by those skilled in the art. In the case of injection of its formulation by needle, the dosage may be - but need not be - in the range of about 10 to about 200 micrograms ("μg") administered once daily, more preferably about 20 to about 100 μg per dose, more preferably Preferably from about 20 to about 50 [mu]g per dose, or most preferably from about 20 to about 40 [mu]g per dose, administered once daily. In addition, those of ordinary skill in the art will appreciate that dosage levels for injectable formulations comprising bone-expanding agents other than PTH[1-34] _NH2 will be consistent with those described herein, said PTH [1-34] Bone-expanding agents other than _NH2 are described in further detail below. PTH[1-34]OH can also be used in the same manner as above, if desired.

Alternative ways of performing method 100 are additionally contemplated to be within the scope of the present invention. Referring now to Figure 5, a vertebra is generally indicated at 50a. Vertebrae 50a also has an osteoporotic fracture, illustrating one type of bone and corresponding condition (ie, fracture) that can be treated by method 100 . However, in this embodiment, to treat vertebra 50a with method 100, step 110 and step 120 are performed substantially simultaneously. Figure 5 shows enhanced or derived bone cement 62a. Figure 3 shows a vertebroplasty needle 54a inserted following a pedicle penetration procedure, the tip of the needle 54a being placed in a vertebral body 58a. Also shown is needle 54a pressing against reinforced bone cement 62a in vertebral body 58a.

An example of the foregoing embodiments includes a method of treating an osteoporotic fracture in the body of an individual in need thereof, wherein bioactive bone cement (hereinafter also referred to as "biomaterial") is delivered to the interior of the bone and administered orally Bone augmentation agents assist the cement to bind from its injected state into a material similar to normal natural bone by promoting bone growth on, in and/or around the particles of the cement so that the additional bone thus formed is encouraged Faster growth with significantly less resorption than methods relying on bone augmentation agents or cements alone.

Another embodiment includes a method of treating an osteoporotic fracture in the body of an individual in need thereof, wherein a biomaterial is delivered into the bone, and a nasally administered augmentation agent is used to assist the biomaterial from its injected state to bind to and Transforms into a material similar to normal natural bone as described above. Yet another example of this embodiment includes a method of treating an osteoporotic fracture in the body of an individual in need thereof, wherein the biomaterial is delivered into the bone and a transdermally administered augmentation agent is used to assist the biomaterial from Its injected state combines and transforms into a material similar to normal natural bone.

Another embodiment relates to a method of treating an osteoporotic fracture in the body of an individual in need thereof, wherein a biomaterial is delivered into the bone and an injected augmentation agent is used to assist in the incorporation and transformation of the biomaterial from its injected state into a material similar to normal natural bone.

Yet a further example of this embodiment includes a method of treating an osteoporotic fracture in the body of an individual in need thereof, wherein the biomaterial is delivered into the bone and the biomaterial is aided with parathyroid hormone ("PTH") From its injected state the material combines and transforms into a material similar to normal natural bone.

Another embodiment includes a method of treating an osteoporotic fracture in the body of an individual in need thereof, wherein a biomaterial is delivered into the bone and recombinant parathyroid hormone ("rhPTH") is used to assist the biomaterial from its injected state Combines and transforms into a material similar to normal natural bone.

A further example of this embodiment of the invention includes a method of treating an osteoporotic fracture in the body of an individual in need thereof, wherein the biomaterial is delivered into the bone and calcitonin is used to assist the biomaterial from its injected state Combines and transforms into a material similar to normal natural bone.

Yet another example of this embodiment includes a method of treating an osteoporotic fracture in the body of an individual in need thereof, wherein the biomaterial is delivered into the bone, and growth hormone is used to assist the biomaterial from its injected state into and Transforms into a material similar to normal natural bone.

Another embodiment includes a method of treating osteoporotic fractures in the body of an individual in need thereof, wherein a biomaterial is delivered into the bone and insulin-related growth hormone is used to assist the biomaterial from its injected state to bind and transform into a similar than normal natural bone material. A still further embodiment includes a method of treating an osteoporotic fracture in the body of an individual in need thereof, wherein a bone cement consisting of calcium phosphate is delivered into the bone and a binding stimulator is used to help the bone cement bind from its injected state Formation and transformation into a material similar to normal natural bone.

Another embodiment includes a method of treating an osteoporotic fracture in the body of an individual in need thereof, wherein a bone cement consisting of calcium hydroxyapatite is delivered into the bone and a binding stimulating agent is used to assist the bone cement from its injected state Combines and transforms into a material similar to normal natural bone.

Yet another embodiment of the present invention includes a method of treating an osteoporotic fracture in the body of an individual in need thereof, wherein a bone cement consisting of calcium sulfate is delivered into the bone, and a binding stimulating agent is used to facilitate injection of the bone cement therefrom The state combines and transforms into a material similar to normal natural bone.

Another embodiment includes a method of treating an osteoporotic fracture in the body of an individual in need thereof, wherein a bone cement composed of calcium aluminate is delivered into the bone, and a binding stimulating agent is used to help the bone cement bind from its injected state into and transformed into a material similar to normal natural bone.

Another example of this embodiment of the invention includes a method of treating an osteoporotic fracture in the body of an individual in need thereof, wherein bone cement composed of bone morphogenetic proteins is delivered into the bone and a binding stimulating agent is used to assist the bone From its injected state the cement binds and transforms into a material similar to normal natural bone.

Another embodiment includes a method of treating a vertebral fracture in an individual in need thereof using a cement delivered to the vertebrae having insulin-related growth factor ("IGF") embedded therein. The method also includes administering calcitonin or PTH or other bone expansion promoting agent using any suitable delivery mechanism, such as oral delivery, nasal delivery, injectable delivery, transdermal delivery, and the like.

Yet another embodiment includes a method of treating an osteoporotic fracture in the body of an individual in need thereof, wherein a biomaterial is delivered into the bone, and recombinant parathyroid hormone ("rhPTH") is delivered with the cement Into the bone, as an accelerator of localized bone growth and cement binding and conversion from its injected state into a material similar to normal natural bone.

Another example of this embodiment of the invention includes a method of treating an osteoporotic fracture in the body of an individual in need thereof, wherein the biomaterial is delivered to the bone, and recombinant parathyroid hormone ("rhPTH") and Insulin-related growth factor is delivered into the bone with the cement, acting as a promoter of local bone growth and cement incorporation and conversion from its injected state into a material similar to normal natural bone.

Another embodiment includes a method of treating an osteoporotic fracture in the body of an individual in need thereof, wherein a biomaterial is delivered into the bone, and recombinant parathyroid hormone ("rhPTH") and insulin-related growth factor are combined with the The cement is co-delivered into the bone as an accelerator of local bone growth and the incorporation and transformation of the cement from its injected state into a material similar to normal natural bone. A systemic bone anabolic stimulator is delivered to the patient at the same time, either orally/intravenously or by some other method, to result in a more general increase in overall bone density.

It should be understood that the embodiments of the invention described above may include the additional step of altering the contents of the marrow cavity in the bone thus treated to remove all or a portion of the stromal cells from the cavity. Administration of a biocompatible material may accomplish this by forcing the cells out of the medullary cavity, or alternatively another method such as flushing may be used to achieve the same purpose.

As shown for example in Figure 6A, bone formation results in femurs that received a biocompatible matrix material and subsequently treated with PTH were significantly better than buffer solution alone (PBS). These results suggest that the combination of BMX with a biocompatible matrix will promote sustained bone expansion, and the addition of PTH further improves this response.

Furthermore, as shown in Figure 6B, BMX + PTH 1-34NH ₂ and either biocompatible material produced better results than the biocompatible material alone after BMX. The results confirmed the observations obtained with calcein labeling as shown in Figure 1A.

Figure 7A illustrates that bone formed in the bone marrow cavity in response to bone marrow removal (BMX) followed by 21 days of PTH treatment was protected by treatment with calcitonin or alendronate given 63 days later, resulting from The fluorescent signal of calcein in is shown. Alendronic acid is a potent antiresorptive agent, and at the doses given, it has a greater protective effect on newly synthesized bone. In contrast, the resected medullary cavity of the femur of rats treated with PHT for 84 days contained very little fluorescent labeling. Calcein was injected on days 9, 8, 2 and 1 before sacrifice of the animals.

Furthermore, calcitonin and alendronate protected bone formed in response to bone marrow removal (BMX) and treatment with PTH for 21 days. As shown in Figure 7A, bone formed in the marrow cavity in response to bone marrow removal followed by 21 days of PTH treatment was protected by calcitonin or alendronate given 63 days later, resulting from the incorporation into mineralized bone. The fluorescent signal of calcein is shown. In contrast, the resected medullary cavity of the femurs of rats treated with PHT for 84 days no longer contained fluorescent labeling.

In addition, Figure 7B shows the results obtained by Micro-CT analysis of bone formed in the marrow cavity in response to bone marrow removal followed by 21 days of PTH treatment followed by 63 days of treatment with the antiresorptive drugs calcitonin or alendronate. Calcitonin protected bone formed in response to marrow removal and treatment with PTH for 21 days, whereas alendronate protected this bone to a greater extent. In contrast, the resected medullary cavity of the femoral diaphysis of rats treated with PHT for 84 days no longer contained radio-dense bone. These structures confirmed that sustained PTH treatment resulted in bone resorption in anatomical regions lacking the cancellous bone network of trabecular bone. However, the administration of bisphosphonates can maintain the newly formed bone at this site.

In a preferred embodiment, the methods of the invention are used in human subjects. However, the invention additionally includes veterinary applications.

In yet another embodiment to those described above, the present invention comprises the additional step of mechanically inducing an increase in osteoblast activity in the subject to be treated, the induction being the same as described above to said subject The introduction of biocompatible materials, such as bone cement, is done in conjunction with the administration of bone augmentation agents, such as bone anabolic agents. The individual steps may be performed in any order, but they are performed in close enough time that the concentration of at least one bone-expanding agent in the bloodstream of the subject is increased and the mechanically induced increase in osteoblast activity in said subject overlap at least in part. In a further optional step, an antiresorptive agent may be administered to the subject for a duration and concentration sufficient to further reduce resorption of bone formed by the synergistic interaction between the various method steps. Another factor that prevents this resorption and thereby maintains the additional bone growth achieved by using the methods of the present invention is the presence of bone cement, a material that acts as a "scaffold" or carrier from which further growth can continue. Once a sufficient amount of bone has formed, antiresorptive agents can be administered to protect the bone that has synthesized.

Mechanical induction can be, but need not necessarily, be achieved by using a method that involves mechanically altering the contents of the bone marrow cavity located in the bone where it is desired to promote and maintain this additional bone growth. Various methods of achieving such alterations in the contents of the bone marrow cavity are described below.

Induction of bone growth may include, for example, generating new or additional bone where such bone growth is not currently occurring, and/or stimulating growth (ie, increasing the rate of growth) of bone already in the process of formation. Without being bound by theory in any way, the applicants believe that the induction of bone growth is due to the combined action of (1) the mechanical induction of osteoblast activity in the subject, and (2) the induction of bone growth in the subject. An increase in the blood concentration of at least one bone anabolic agent. Bones described as being formed by the method of the present invention are not limited to trabecular bone, but are also considered to include any one or more of the following additional "types" of bone: compact bone, cortical bone, and/or lamellar bone bone, and this applies throughout this specification.

In a preferred embodiment of the invention, the mechanical induction of increased osteoblast activity can be obtained by a procedure of bone marrow flushing and ablation. Again, applicants do not wish to be bound by theory in any way, but believe that bone marrow flushing or a mechanical process results in the formation of a blood clot in the bone marrow cavity, which, through a cascade of biochemical reactions, promotes increased osteoblast activity in the subject. Increase.

In another embodiment, increased osteoblast activity may alternatively be obtained by coupling mechanical induction with another form of induction, such as biochemical induction. Such biochemical induction can be obtained by administering to a subject, for example, an amount of a blood factor such as Factor ("F") VII, fibrinogen or fibrin, Factor Vila, or a combination thereof. Following tissue or vessel injury, coagulation is initiated by the binding of plasma FVII/FVIIa to tissue factor (thromboplastin). This complex (FVII/FVIIa+thromboplastin) initiates a cascade of events that leads to activation of the coagulation cascade, culminating in fibrin deposition and platelet activation. This complex series of events may contribute in part to the stimulation of osteoblasts in the bone marrow. Factor VII and VIIa are commercially available eg from the company Novo Nordisk.

The increase in osteoblast activity obtained with the methods of the present invention can be attributed to a number of factors, including, but not necessarily limited to, (1) osteoblast differentiation, i.e., the production of additional osteoblasts, (2) increase of already existing osteoblasts. The activity and/or effectiveness of osteocytes to induce bone formation in a subject, and (3) a combination of both. In a preferred embodiment of the invention, the increase in osteoblast activity will include all of the above functions.

In one embodiment of the invention, the method further comprises "targeting" one or more specific bones of the subject to induce bone growth. This targeting is achieved by mechanically altering the contents of the marrow cavity in each targeted bone to induce increased osteoblast activity therein.

The method according to the invention can thus be used not only for bone repair, i.e. as in the case of trauma-induced fractures, but also for strengthening bone in a site-specific manner in the case of individuals who have undergone dual-energy X-ray absorptiometry ("DEXA") or other techniques demonstrating the need to increase bone mass and/or density to prevent fractures (such as in individuals with osteoporosis), or who suffer from chronic pain due to bone weakening attributable to conditions such as vertebral fractures . Furthermore, the method of the present invention additionally helps to provide (and maintain) the new bone needed to act as an anchor for prosthetics such as artificial hips, knees and shoulders and/or implants such as dental implants. New bone growth can be targeted to bones at risk of fracture to improve strength and reduce fracture risk.

In one embodiment of the invention, a bone anabolic agent may be administered to a subject while mechanically inducing osteoblast activity (whether by increasing osteoblast formation and/or by increasing bone formation from existing osteoblasts). In the therapeutic context, this mechanical induction can be achieved, for example, by altering the bone marrow cavity. In preferred embodiments, the marrow and/or other components of the medullary cavity are removed under pressure (eg, by changing the relative pressure inside and outside the medullary cavity), eg, by flushing the medullary cavity and removing stromal cells.

In another embodiment, the bone anabolic agent is administered after such mechanical induction. In another embodiment, the bone anabolic agent may be administered prior to mechanical induction such that high levels of the bone anabolic agent are already present at the time of mechanical induction, which levels may then be maintained or intermittent for a sustained period of time.

As discussed above, bone anabolic agents may be administered orally, intravenously, intramuscularly, subcutaneously, via implants, transmucosally, transdermally, rectally, nasally, by depot injection, or via Inhalation and pulmonary absorption. In another embodiment, the bone anabolic agent may be administered as a delayed release formulation once, multiple times, or over one or more prolonged periods. Preferably, high blood levels of the anabolic agent are maintained at least intermittently for about 14 to 365 days, more preferably about 30 to 180 days after mechanical induction. Intermittent administration of parathyroid hormone such as PTH[1-34] _-NH2 can be given daily or weekly, resulting in peak blood concentrations returning to baseline between doses, but still causing bone anabolic The cyclical increase in blood levels of , which overlaps with the initially mechanically induced increase in osteoblast activity, is maintained at least in part by an anabolic agent after mechanical induction.

In yet another embodiment, the anabolic agent is selected from the group consisting of parathyroid hormone (PTH), an anabolic vitamin D analog, a low-density lipoprotein receptor-related protein 5 (LRP5) activator, or inhibition of the binding of sclerostin to LRP5 non-genomic activator of estrogen-like signaling (ANGELS), bone morphogenetic protein (BMP), insulin-like growth factor (IGF), fibroblast growth factor (FGF), sclerostin, leptin, prostaglandins , inhibin, strontium, growth hormone, growth hormone releasing factor (GHRF), hepatocyte growth factor (HGF), calcitonin gene-related peptide (CGRP), parathyroid hormone-related peptide (PTHrP), transforming growth factor (TGF )-PGE-2 and stable analogs thereof and combinations thereof. The term parathyroid hormone as used herein includes, but is not limited to, native parathyroid hormone, truncations of native parathyroid hormone, amidated truncations of native parathyroid hormone, amidated native parathyroid hormone, and derivatives thereof combination.

(特立帕肽)。其他适用于本发明的骨合成代谢剂包括但不限于天然甲状旁腺激素的酰胺化截短物、PTH[1-30]NH₂、PTH[1-31]NH₂、PTH[1-32]NH₂、PTH[1-33]NH₂、PTH[1-34]NH₂以及它们的组合。在一个优选的实施方案中，骨合成代谢剂是PTH[1-34]NH₂。制备截短型甲状旁腺激素的方法描述于Mehta等人的第6,103,495号美国专利。此外，对这种截短型甲状旁腺激素进行酰胺化的方法，在例如Bertelsen等人的第5,789,234号美国专利和Gilligan等人的第6,319,685号美国专利中提供。这些专利每一个的内容都专门通过引用并入本文。In one embodiment, the bone anabolic agent is truncated PTH in the free acid form [1-34]. An FDA-approved pharmaceutical formulation of this material is commercially available from Eli Lilly & Co. under the tradename

(teriparatide). Other bone anabolic agents suitable for use in the present invention include, but are not limited to amidated truncations of natural parathyroid hormone, PTH[1-30] _NH2 , PTH[1-31] _NH2 , PTH[1-32] _NH2 , PTH[1-33] _NH2 , PTH[1-34] _NH2 , and combinations thereof. In a preferred embodiment, the bone anabolic agent is PTH[1-34] _NH2 . Methods for preparing truncated parathyroid hormone are described in US Patent No. 6,103,495 to Mehta et al. In addition, methods for amidating such truncated parathyroid hormones are provided, for example, in US Patent No. 5,789,234 to Bertelsen et al. and US Patent No. 6,319,685 to Gilligan et al. The contents of each of these patents are expressly incorporated herein by reference.

In one embodiment of the method of the invention, sufficient amount of the preferred truncated parathyroid hormone (see discussion above) is administered to the subject to achieve and thereafter maintain its pulsatile blood concentration in the subject From about 50 to about 350 pg/ml, preferably from about 100 to about 200 pg/ml, most preferably about 150 pg/ml. In another embodiment, the blood concentration of parathyroid hormone in the subject is increased to its preferred level no later than 7 days after the mechanical alteration of the bone marrow cavity contents. It is well known in the art that appropriate dosages of PTH bone anabolic agents must be calculated to achieve the aforementioned blood levels. For example in the case of injectable formulations, dosages (based on pure weight of active hormone) administered to eg human subjects may be those taught in the literature regarding the bone anabolic activity of these various agents. Such doses, if administered parenterally, may but need not be in the range of about 10-200 μg administered once daily, more preferably about 20-100 μg per dose, most preferably about 20-50 μg per dose. Dosage levels for injectable formulations containing bone anabolic agents other than parathyroid hormone-based agents described above are consistent with known blood levels required to elicit an anabolic response in humans.

In a further embodiment of the invention, an object configured or adapted to physically alter the contents of the medullary cavity to stimulate osteoblast activity in the medullary cavity is inserted into the marrow of the bone targeted for enhanced bone formation cavity, achieving mechanical induction of osteoblast activity. In another embodiment, the mechanical alteration may comprise removal of at least a portion of the contents of the medullary cavity. A suitable method is to lavage the bone marrow cavity with solution to remove stromal cells. In certain embodiments, the use of biocompatible materials can be used to deplete bone marrow cells for induction of osteoblastic activity.

In yet a further embodiment, the methods of the invention additionally comprise administering an antiresorptive agent to the subject for a time and at a concentration sufficient to substantially prevent resorption of new bone produced by osteoblastic activity. In one embodiment, the antiresorptive agent may be administered at the same time as the bone anabolic agent. In another embodiment, the antiresorptive agent is administered after the bone anabolic agent is administered. In a further embodiment, the administration of the antiresorptive agent can be initiated during the administration of the bone anabolic agent, which administration can then be continued after the administration of the bone anabolic agent has ended.

In another embodiment of the invention, a single agent having both bone anabolic and antiresorptive properties may be administered. Examples of such materials include, but are not limited to, estrogens, strontium ranelate, and selective estrogen receptor modulators (SERMS).

In one embodiment of the method of the invention, the antiresorptive agent may be selected from the group consisting of human calcitonin, salmon calcitonin ("sCT"), eel calcitonin, eltonin, porcine calcitonin, chicken calcitonin calcitonin, calcitonin gene-related peptide (CGRP), and combinations thereof. In a preferred embodiment, the antiresorptive agent is salmon calcitonin. When used as an antiresorptive agent, calcitonin blood levels are preferably in the range of about 5-500 pg/ml, more preferably about 10-250 pg/ml, most preferably 20-50 pg/ml. Furthermore, in the case of eg injectable formulations, the human dosage levels of the subject calcitonin agents required to achieve the above blood levels may be the levels taught in the literature concerning the use of these materials as anabolic agents. Such doses may, but need not, be in the range of about 5-200 μg administered once daily, more preferably about 5-50 μg, most preferably 8-20 μg, by weight of pure drug, administered daily. Administration of salmon calcitonin (sCT) by an alternative route, ie nasal or oral administration, would require higher doses than those discussed above.

其包括利塞膦酸钠作为其活性成分，典型公认剂量为每日一片5mg片剂或者每周一片35mg片剂；(3)Eli Lilly & Co.出售的

其包括盐酸雷洛昔芬作为活性成分，这个制剂的典型公认剂量为每日一片60mg片剂；和(4)可获自Merck Pharmaceuticals的

其包括阿仑膦酸作为活性成分，这个材料的典型剂量为10mg/天或70mg/周。另外的双膦酸盐包括

(Proctor Gamble Aventis)、

(GSK Roche)和(Novartis)。Alternatively, a variety of additional antiresorptive agents (ie, antiresorptive agents other than calcitonin) may be used in the methods of the invention. These primarily include hormone replacement therapy (HRT) agents such as selective estrogen receptor modulators (SERMS), bisphosphonates, cathepsin K inhibitors, strontium ranelate, and various combinations thereof. Specific examples of additional antiresorptive agents include, but are not limited to: (1) ® , available from Wyeth Laboratories It includes estrogen as the active ingredient, and the typical accepted dose is one 0.625 mg tablet daily; (2) available from Proctor & Gamble as

It includes risedronate sodium as its active ingredient, and a typical accepted dose is one 5 mg tablet daily or one 35 mg tablet weekly; (3) Sold by Eli Lilly & Co.

It includes raloxifene hydrochloride as an active ingredient, and the typical accepted dose of this formulation is one 60 mg tablet per day; and (4) Raloxifene available from Merck Pharmaceuticals

It includes alendronic acid as the active ingredient, a typical dose of this material being 10 mg/day or 70 mg/week. Additional bisphosphonates include

(Proctor Gamble Aventis),

(GSK Roche) and (Novartis).

Unless otherwise indicated or apparent from the context, dosages herein refer to the weight of active compound unaffected by pharmaceutical excipients, diluents, carriers, or other ingredients, but which are generally included in dosage forms useful in the methods of the invention. of types. Any dosage form commonly used in the pharmaceutical industry (i.e. capsules, tablets, injections, etc.) is suitable for use in the present invention, and the terms "excipient", "diluent" or "carrier" include those commonly used in the pharmaceutical industry to contain active ingredients. together with inactive ingredients. For example, typical capsules, pills, enteric coatings, solid or liquid diluents or excipients, flavors, preservatives and the like are included. In addition, it should be noted that for all doses recommended herein, the attending clinician should monitor individual patient responses and adjust doses accordingly.

Antiresorptive agents can be administered orally, intravenously, intramuscularly, subcutaneously, via implants, transmucosally, rectally, nasally, by depot injection, by inhalation and pulmonary absorption, or transdermally. In addition, antiresorptive agents may be administered once, multiple times, or over one or more prolonged periods.

While the invention has been described in terms of specific embodiments thereof, it is apparent that many other changes and modifications and other uses will be apparent to those skilled in the art. Accordingly, the invention is not to be limited by the specific disclosure herein, but only by the appended claims.

Claims (31)

1. the method for an amplification bone in the curee who needs is arranged, described method comprises:

(a) mechanically induce the active increase of osteoblast among the described curee;

(b) in the inside of having induced the active bone that improves of osteoblast in described curee, the biocompatible materials of capacity is installed, to form support in described inside bone, described support serves as the new osteoplastic carrier in described inside; With

(c) at least a bone amplification agent with capacity gives described curee, improving the haemoconcentration of at least a bone anabolic agent among the described curee, among the wherein said curee among the raising of the haemoconcentration of anabolic agent and the described curee the active raising of osteoblast overlap at least in time.

2. the process of claim 1 wherein that described biocompatible materials is selected from bioactive bone cement, bone morphogenetic protein, polymer, Fibrinogen, synthetic fibrin, collagen gel, collagen adds hydroxyapatite suspension and their combination.

3. the method for claim 2, wherein said biocompatible materials is a bioactive bone cement, described bone cement is selected from calcium phosphate, calcium hydroxy apetite, calcium sulfate and calcium aluminate.

4. the process of claim 1 wherein that described bone amplification agent is the bone anabolic agent.

5. the method for claim 4, wherein said bone anabolic agent is selected from parathyroid hormone (PTH), the anabolism novel vitamin D analogues, the bonded inhibitor of LDH receptor related protein 5 (LRP5) activator or sclerosis albumen and LRP5, the activator (ANGELS) of non-genomic group estrogen-like signal transduction, bone morphogenetic protein (BMP), insulin like growth factor (IGF), fibroblast growth factor (FGF), leptin, prostaglandin, inhibin, strontium, growth hormone, somatotropin releasing factor (GHRF), hepatocyte growth factor (HGF), calcitonin-gene-related peptide (CGRP), parathyroid hormone-related peptide (PTHrP), transforming growth factor (TGF)-β 1 and their combination.

6. the method for claim 5, wherein said bone anabolic agent is a parathyroid hormone, and described hormone is selected from the natural parathyroid hormone of amidatioon truncate, amidatioon and their combination of the truncate of natural parathyroid hormone, natural parathyroid hormone, natural parathyroid hormone.

7. the method for claim 6, wherein the described parathyroid hormone with capacity gives described curee, and its pulsatile blood concentration is about 50-350pg/ml in described curee to reach.

8. the method for claim 6, the parathyroid hormone of wherein said capacity is the PTH hormone of the pure weight of the about 10 μ g-10mg of every dosage.

9. the method for claim 6, wherein said parathyroid hormone gives by injection, and the parathyroid hormone of described capacity is the about 10-200 μ of every dosage g.

10. the method for claim 6, wherein said bone anabolic agent is the PTH[1-34 of free acid form].

11. the method for claim 6, the amidatioon truncate that wherein said bone anabolic agent is natural parathyroid hormone, described truncate is selected from PTH[1-30] NH ₂, PTH[1-31] NH ₂, PTH[1-32] NH ₂, PTH[1-33] NH ₂, PTH[1-34] NH ₂And their combination.

12. the process of claim 1 wherein that described bone amplification agent is at least a medicament that causes the level raising of the endogenous anabolic agent among the described curee.

13. the method for claim 12, the medicament that the wherein said expression that causes the endogenous bone anabolic agent among the described curee improves are selected from calcium and separate agent and anti-sclerosis protein antibodies.

Give described curee 14. the method for claim 1, described method further comprise with anti-absorbent, described anti-absorbent is to be enough to preventing that the basically amount that described new bone growth absorbs from giving.

15. the method for claim 14, wherein said anti-absorbent are Diphosphonate or the calcitonin that is selected from human calcitonin, salmon calcitonin see calcimar, HC 58, elcatonin, pig calcitonin, chicken calcitonin, calcitonin-gene-related peptide (CGRP) and their combination.

16. the method for claim 15, wherein said anti-absorbent is a salmon calcitonin see calcimar, and wherein said salmon calcitonin see calcimar gives described curee with the haemoconcentration that continues basically that can realize it as calculated in the amount of about 5-500pg/ml.

17. the calcitonin of the method for claim 16, the amount of the wherein said salmon calcitonin see calcimar pure weight of about 5 μ g-5mg that is every dosage.

18. the method for claim 16, wherein said salmon calcitonin see calcimar gives by injection, and the amount of described salmon calcitonin see calcimar is the about 5 μ g-200 μ g of every dosage.

19. the process of claim 1 wherein that described bone amplification agent is a parathyroid hormone, and wherein after described mechanical induction earlier than 7 days, the haemoconcentration of the described parathyroid hormone among the described curee is brought up to the level of about 50-350pg/ml.

20. the method for claim 1, described method are included in the extra bone that forms capacity in described curee's the jaw district in addition, provide anchor thing to give the dental implant that is implanted in the described jaw district.

21. the method for claim 1, described method are included in described curee in addition is one or morely formed the extra bone of capacity in the targeting bone, describedly be able to firm anchor by the prosthetic appliance in the targeting bone and thereon so that be implanted at least one.

22. the method for claim 1, described method are included among the described curee the extra bone that forms capacity in addition, the hollow in described extra bone to serve as anchor, the firm anchor of scalable insert thing.

23. the method for claim 1, described method comprises that further at least one vertebra of the described curee of targeting forms to carry out supernumerary bone, wherein the bone with capacity is added to described at least one vertebra, makes described curee exempt basically because the chronic pain of vertebra due to cracked.

24. the process of claim 1 wherein that at least one vertebra of described curee extra bone makes its stable amount form to be enough to reinforce described at least one vertebra.

25. the process of claim 1 wherein that described biocompatible materials is administered to by injection is selected from the following position: proximal femurs, aitch bone, distal radius, near-end humerus, calcaneus, rib, tibia and rumpbone.

26. the process of claim 1 wherein that described bone amplification agent gives to be selected from following mode: oral, per nasal, percutaneous, per rectum, subcutaneous and intravenous.

27. one kind in order to promote and to keep lacking bone growth in the inside of bone of enough trabecular bone supports that to prevent the wherein medicine box of the absorption of formed new bone basically, described medicine box comprises:

(a) at least one wherein has at least a container of biocompatible materials that is suitable for forming in described inside bone the support of additional quantity;

(b) at least one wherein has the container of bone amplification agent; With

(c) be used for changing at least one by the mechanical alteration device of the medullary cavity content of targeting bone.

28. the medicine box of claim 27, wherein said biocompatible materials is a bioactive bone cement

29. the medicine box of claim 27, wherein said bone amplification agent is the bone anabolic agent.

30. the medicine box of claim 27, described medicine box further comprise at least one container that at least a anti-absorbent is wherein arranged.

31. the medicine box of claim 27, described medicine box further comprise the removal device in order at least a portion content of removing described medullary cavity.

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