JP2010526064A - Methods and compositions for nurturing and preserving bone tissue growth - Google Patents

Abstract

  A method for increasing bone tissue in a patient who requires an increase in bone tissue, wherein a sufficient amount of a biocompatible material is introduced inside the patient's bone tissue to form a scaffold within the bone tissue. Wherein the scaffold serves to assist in the formation of new bone within the bone tissue, and the patient has an increased blood concentration of at least one anabolic agent in the patient. Administering a sufficient amount of at least one bone tissue augmenting agent. The method further includes administering to the patient an amount of at least one resorption inhibitor sufficient to substantially prevent resorption of new bone tissue growth. In another embodiment, the method further comprises the step of mechanically inducing an increase in osteoblast activity in the patient, wherein the increase in blood concentration of the anabolic agent and the increase in osteoblast activity are At least partially overlap in time.

Description

The present invention relates generally to methods and compositions for bone tissue growth and preservation in patients. More specifically, the present invention relates to rapid bone tissue at locations such as, for example, fracture sites, regions of skeletal areas with reduced bone density, and / or sites of long bones lacking cancellous bone structure. Foster the growth of additional bone tissue at such locations by providing the formation and subsequent endoskeleton or scaffold on which the newly produced bone tissue is fixed and grown Includes preservation of new bone tissue formed in between. A resorption inhibitor can optionally be administered to reduce the gradual resorption of newly formed bone tissue.

BACKGROUND OF THE INVENTION Skeletal bone tissue is not completely solid. For example, outer bone tissue, such as cortical bone, is substantially solid but has a few Hervas tubes. However, there is cancellous bone tissue known as cancellous bone (or trabecular bone) inside cortical bone. The cancellous bone tissue consists of a trabecular bone having a honeycomb-like structure, and the trabecular bone is filled with a plurality of spaces or cavities with fluid bone marrow, stem cells, and several fat cells. In these medullary cavities, among other things, various highly differentiated cells (osteoclasts) that help destroy existing bone tissue, as opposed to broken bone or trauma and disease There are cells that produce new bone tissue (eg, osteoblasts) to replace bone lost due to factors.

  As mentioned above, the physical structure of bone tissue is compromised for a variety of reasons including trauma and disease. One of the most common bone diseases is osteoporosis. Osteoporosis is characterized by a low mass of bone tissue and structural deterioration of the bone tissue, which results in increased bone fragility and in particular increased sensitivity to the hip spine and wrist fractures. Osteoporosis occurs where there is an imbalance where the rate of bone tissue resorption exceeds the rate of bone tissue formation. This is due in part to the fact that osteoblasts take 6 days to reconstitute the amount of bone destroyed by osteoclasts in 3 days. For example, by age 55, an average osteoporotic woman has already lost 30% of bone mass.

  Osteoporosis accelerates rapidly in menopause and is the third leading cause of death in women over 70 years of age. The disease also afflicts men, accounting for 20% of all osteoporosis patients. By the age of 75, about 90% of all women and about 33% of all men will have osteoporosis. The disease results in 1.5 million fractures per year, and as a result, annual medical costs in the United States exceed $ 1.8 million. One in two women over the age of 50 and one in eight men will have osteoporotic fractures in their lifetime. Of these, one of five who suffered from a hip fracture cannot grow for more than one year. To date, less than 10% of affected individuals have been treated for osteoporosis with prescription drugs.

These prescription drugs typically include at least one bone tissue augmenting agent. As used herein, the term “bone tissue augmenting agent” includes, but is not limited to, bone tissue anabolic agents and agents that increase the blood levels of endogenous bone tissue anabolic agents produced within a patient. Bone tissue augmenting agents known as bone tissue anabolic agents are known in the art. Bone tissue anabolic agents are generally parathyroid hormone and various parathyroid hormone fragments in the form of amidated or free acid, PTHrP and their analogs, prostaglandin E-2, bone morphogenic protein,
Including but not limited to IGF-1, growth hormone, fibroblast growth factor TGF and others. On the other hand, drugs that increase the expression of endogenous bone tissue anabolic agents include, but are not limited to, calcilytic agents and antibodies to sclerostin. A calcilytic agent typically, but not necessarily, contains an agent that limits the binding of calcium to its receptor, thereby causing the release of endogenous parathyroid hormone. Examples of these materials are described in US Pat. Nos. 6,362,231, 6,395,919, 6,432,656 and 6,521,667, the contents of which are hereby incorporated by reference. Cited in and incorporated by reference.

  Administering bone tissue anabolic agents, such as those described above, for example for the purpose of increasing bone density, however, often involves long-term treatment plans, which are associated with patient compliance issues. In addition, such treatment methods target the entire skeletal system to cause systemic effects, and thus are not targeted, resulting in an effect on one or more specific bone tissues, It cannot be done again.

  Thus, for example, a quicker, more targeted method that helps induce bone tissue formation and preserves the growth of new bone tissue produced thereby in patients with reduced bone tissue mass Some of the co-inventors of the present invention have developed methods for nurturing and preserving bone tissue formation that overcome the disadvantages of the prior art described above. The method mechanically induces an increase in osteoblast activity in one or more targeted bones of a patient in need of additional bone tissue growth and coupled thereto Increasing the blood concentration of at least one bone tissue anabolic agent in a patient, wherein the steps described above can be performed in any order, these include increasing the concentration of bone tissue anabolic agent, and The mechanical induction of increased osteoblast activity occurs at a time sufficiently close to overlap at least partially. Such methods are described, for example, in US patent application Ser. No. 11 / 128,095 filed May 11, 2005, and US continuation-in-part application No. 11 / 267,987 filed Nov. 7, 2005. ing. The contents of both of these applications are incorporated herein by reference. As described above, the method can specifically target specific bone tissue, for example, for the effects of repair, reinforcement, remodeling and / or remodeling.

  New bone tissue so that the method described above provides a sufficient amount of cancellous bone in a targeted location for the growth of additional bone tissue and is provided as a skeleton to assist in new growth. New bone tissue produced by the action of bone tissue anabolic agents alone, even as it is found to be particularly effective in the growth and preservation of bone, serves as a scaffold, whether it is endogenous or not It is not ideal for replacing bone in places where there is a lack of sufficient amount of cancellous bone. Furthermore, the use of PTH and other anabolic agents is not sufficient to fill the gaps in the trabecular bone, which are holes due to increased bone tissue resorption. Some bone tissue produced by augmenting agents (including but not limited to anabolic agents) may be lost by such resorption where there is a gradual lack of bone scaffold material as described above. . Previous efforts to prevent or at least minimize such reabsorption include the administration of reabsorption inhibitors known in the art. These agents include, for example, human calcitonin, salmon calcitonin, eel calcitonin, elcatonin, porcine calcitonin, chicken calcitonin, SERMS (selective estrogen receptor modulator), bisphosphonates, strontium ranelate and combinations thereof. It is not limited to. Administration of such resorption inhibitors can protect newly formed bone tissue. However, some or all of the new bone formed in the early explosive growth promoted by the presence of the anabolic agent may nevertheless be resorbed by the patient himself. In this way, new bone effects such as increased skeletal strength and / or reinforcement are compromised.

  However, the present inventors have discovered that by introducing a material that forms a biocompatible matrix at such a specific location, the loss of newly targeted bone tissue is prevented. Because the material provides assistance that allows additional bone growth. Furthermore, it has been found that the introduction of such a biocompatible matrix makes it possible to synthesize bone tissue at a location within the diaphysis of a long bone, such as the upper arm.

  For illustrative purposes, one of the typical areas where bone damage due to such thinning, and the accompanying thinning, including fractures associated therewith, is difficult to solve. The vertebrae. Vertebroplasty and kyphoplasty are now commonly used in the United States, but are a surgical tool for increasing the spine and further address the pain associated with spinal compression fractures. Both of these procedures use X-ray guidance and transpedicular or parapedicular procedures to access the vertebral body to inject liquid cement. The cement is then consolidated to weaken and increase painful vertebrae. The simplest procedure is vertebroplasty. This technique is discussed, for example, in US Pat. No. 6,273,916, the contents of which are incorporated herein by reference. A more recent technique that has become more common is vertebroplasty, which involves inflating the balloon to restore height, and putting bone cement into the cavity formed by the balloon. inject.

A very common bone cement used in these methods is polymethyl methacrylate ("PMMA"). The use of PMMA has been published in various professional journals: (a) “Is percutaneous vertebroplasty without venography pre-treatment safe? Evaluation ”, 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 cement: physiochemical in percutaneous vertebroplasty” And consideration of biochemical properties ”, Matthew J. Provenzano, Kieran PJ Murphy, and Lee H. Riley III, AJNR Am J Neuroradiol 25: 1286-1290, August 2004 (“ Provenzano ”); (c)“ acrylic ” Results of clinical use of bone cement in chemical and image-guided therapy ”, David A. Nussbaum, MS, Philippe Gailloud, MD, and Kieran Murphy, MD., J Vasc Interv Radiol 2004; 15 Page 1. (“ Nussbaum ”) . The contents of these papers are incorporated herein by reference.

  PMMA is an acrylic bone cement. This is not sticky and does not gradually dissolve into the bone tissue, however, it is extremely strong. For example, PMMA acts like a rebar in cement in a structure. However, the use of PMMA has important drawbacks. It is known that PMMA removes or reduces the force that maintains bone density by replacing the role of the trabecular structure around it. The charge contributing to the growth of bone tissue is removed or reduced.

  Furthermore, monomer solutions for dissolving PMMA powders can be toxic and are associated with complications such as death and cardiac arrest (see Nussbaum literature). In addition, the high compressive strength of PMMA provides a high force that does not fit into the adjacent vertebrae, causing fractures in the adjacent vertebral bodies. This is because the vertebral body becomes too stiff due to the injection of PMMA. These adjacent fractures occur in 8 to 10% of this section.

Promising alternatives to PMMA are biologically active bone cements or biocompatible polymers. Biologically active bone cement can remove some of the difficulties faced with the use of PMMA. For example, biologically active bone cement has a lower strength compared to PMMA. Thus, when they are injected, the vertebral body becomes less rigid. However, for example, the use of vertebral augmenting agents has many problems inherent to it.
For example, biologically active bone cements are very difficult to inject, they lack natural radiation concentrations, and they usually do not dissolve well over months or years. In addition, some biologically active bone cements take several hours to set and become safe. More generally, some of these cements have been reported dead. This may be related to the pH of the injected cement or may be related to calcium leaking into the circulatory system resulting in disseminated solidification. However, there is currently little knowledge on how to use biologically active bone cement in spinal augmentation procedures.

  The biologically active cement used for spinal augmentation is calcium phosphate. Calcium phosphate cement consists of a powder and a solution for dissolving the powder. They are widely used in hip, spine and wrist surgery, as well as cranial restriction. There are two different families of calcium phosphate cement. One group undergoes an exothermic reaction while the other group undergoes an endothermic reaction. One group belongs to a family called bruschite cement. The other group belongs to the family that forms hydroxyapatite, which is ultimately the precursor of bone tissue. When the calcium phosphate powder and aqueous solution are mixed, it becomes a paste that hardens in minutes to hours. They are therefore not suitable for injection and not suitable for visualization under X-ray guidance and are therefore difficult to use in spinal augmentation techniques. In addition, as they reach bone tissue, they affect the osteoblasts and osteoclasts remaining in the trabecular structure. If the trabecular structure does not remain, the surrounding bone cement dissolves into the endosteum on the bone surface. However, the bone cement located in the vertebral body mass remains in an unchanging shape, which is a brittle ceramic with low tension and low compression density, which can have long-term negative effects.

  In view of the shortcomings of the prior art described above, a method that makes bone formation faster and more effective in bone lacking the bone scaffolding that makes up the trabecular bone, and that is the new bone produced in this way A method with a certain degree of conservation promotion is needed for those who have been in the field for many years. As will be described later, the present invention brilliantly satisfies these required functions.

  The object of the present invention is therefore to induce a relatively rapid growth of the target bone tissue in all new and non-obvious, necessary sites and preserve the new bone tissue growth obtained in the meantime, And providing a way to increase.

  In general, as described in further detail below, the present invention introduces biologically active cement or other matrix-forming material into the bone, causing new bone growth in that location, As a result, a method is provided for the cement or other matrix material to be blended into existing bone structure with new bone. In one embodiment of the invention, removal of stromal cells, for example by irrigation, is used as a stimulation of targeted new bone growth, wherein the bone tissue augmentation composition is, for example, bone tissue that prolongs the response An anabolic agent, and here the matrix-forming material fills the space lacking trabecular bone inside the bone, and where such trabecular bone is not sufficient, and such trabecular bone is completely absent Provides a scaffold for new bone tissue growth where For example, the periodic paradigm of bone marrow irrigation performed after resorption inhibition therapy, and the administration of anabolic agents performed therewith, and the introduction of a biocompatible matrix within bone tissue are envisioned in the present invention. The

In one embodiment of the present invention, the present invention provides a method for increasing bone tissue in a patient with poor bone tissue. Here, the method includes administering a sufficient amount of a biocompatible material within the bone tissue of the patient to form a scaffold within the bone. The scaffold here assists in the formation of new bone within the bone tissue. The method then includes administering to the patient a sufficient amount of at least one increasing agent such that the blood concentration of the at least one anabolic agent is increased in the patient.

  In another embodiment, the present invention provides a method for increasing bone tissue in a patient with poor bone tissue. Here, the method mechanically induces an increase in osteoblast activity in the patient, and places a scaffold inside the bone tissue in the patient in which the increase in osteoblast activity is induced. Injecting a sufficient amount of biocompatible material to form, wherein the scaffold serves to help form new bone tissue within the bone tissue, and to the patient, at least in the patient Administering at least one bone tissue augmenting agent in an amount sufficient to increase the concentration of one bone tissue anabolic agent, wherein the increase in blood concentration of bone tissue anabolic agent and osteoblast activity in the patient; The rise includes at least partially overlapping in time.

  Furthermore, in one embodiment, the present invention provides for bone growth within bone tissue that lacks a sufficient amount of trabecular scaffold to substantially prevent resorption of new bone tissue formed therein. Is a kit for nurturing and storing The kit includes at least one container having at least one biocompatible material and at least one container having a bone tissue anabolic agent applied to form an additional amount of scaffold.

  In one embodiment, the present invention also provides for the growth of bone tissue within bone tissue that lacks sufficient trabecular scaffolding to inhibit resorption of substantially newly formed bone tissue. It is a kit for breeding and protection. The kit is applied to form an additional amount of scaffold within bone tissue, at least one container having at least one biocompatible substance, and at least one container having a bone tissue augmenting agent; And a container containing a mechanical modification device that alters the contents of the medullary cavity of at least one targeted bone tissue.

  The present invention will now be described, by way of example only, with reference to specific embodiments and the accompanying drawings.

FIG. 1A is a cross-sectional view of the midshaft of the rat femur after administration for 21 days and 84 days, respectively. Each group consists of (a) control / no bone marrow removal (“BMX”) or anabolic agent, (b) BMX / bone marrow removal alone, and (c) BMX + PTH-bone marrow removal and PTH1-34 NH ₂ for 21 days or 84 Daily administration. In addition, rats received a fluorescent dye called calcein 9, 8, 2 and 1 day before sacrifice. Calcein dissolves in bone tissue and is used as an indicator of bone tissue growth and petrification. FIG. 1B represents the results of using an imaging technique called micro-CT in the same group of animals. This technique provides high resolution of the bone marrow cavity of the femoral diaphysis in control, BMX, and BMX + PTH1-34 NH ₂ rats, administered PBS (buffer) or PTH for 21 or 84 days, respectively. FIG. 2 illustrates a method of bone tissue augmentation according to one embodiment of the present invention. The method is a biocompatible bone cement, but not necessarily, administration of a biocompatible matrix material and concomitant bone tissue augmentation, such as a bone tissue anabolic composition With administration of the drug. FIG. 3 represents an axial view of a vertebra having an osteoporotic fracture. Here, the vertebra is administered with a biocompatible matrix material (eg, biologically active bone cement), which is one implementation of the steps shown in FIG. A biocompatible material is injected into the space lacking cancellous bone to provide a scaffold for the formation of persistent bone tissue. FIG. 4 represents the administration of a bone tissue augmenting agent such as a bone tissue anabolic agent. This is then done as one of the steps shown in FIG. The biocompatible matrix can include an anabolic agent associated with or intermingled with the matrix. Furthermore, the anabolic agent can be administered to the patient alternately systemically. FIG. 5 represents an axial image of a vertebra with osteoporosis. Here, the vertebrae are administered a biocompatible matrix slurry, which is performed as one of the steps shown in FIG. And according to another embodiment of the present invention. In this example, residual cancellous bone that is affected by the combined effects of, for example, mechanically inducing increased osteoblast activity through irrigation of at least a portion of the bone marrow cavity and concomitant administration of an anabolic agent Exists. However, in areas where complete trabecular bone is lacking, the introduction of biocompatible materials fills the gaps and provides the skeleton necessary for the sustained growth of new bone. FIG. 6A shows the extent of sustained bone growth achieved on day 84 after administration of the biocompatible material. In this example, cementite (Cementech LV, non-stoichiometric hydroxyapatite, prepared by reacting the acid and base calcium phosphate in the presence of an aqueous solution. Teknimid, 65500 VIV en Biggore, France) or Pepgen- 15 (High purity inanimate bovine transplant material, radiopaque and peptide-enhanced to reproduce autogenous bone. Dentsply Friadent CeraMed Lakewood, Colorado). All samples were taken from the femur where BMX was performed. Groups are biocompatible matrices (Cementec or Pepgen) with or without 84 days of administration of BMX or PTH after 84 days of administration of the anabolic agent or BPS (buffer) shown in the first row. -15) BMX after administration of the slurry. FIG. 6B shows the results obtained from a group of animals similar to that reported in FIG. 6A using the micro-CT imaging technique. This imaging technique is followed by high resolution analysis of the bone marrow cavity of the femoral shaft obtained from BMX + PBS or PBX + PTH treatment, for example in a process such as removal, resulting in increased osteoblast activity, Provided in comparison to the femur into which a biocompatible substance (Cementec or Pepgen-15) has been introduced into the medullary canal. FIGS. 7A and 7B show the effects resulting from the administration of alendronic acid, a resorption inhibitor, to preserve bone tissue formed by the method according to the present invention. The following treatment modalities are included: (a) BMX + PTH1-34 NH ₂ for 21 days + PBS (buffer) for 22-84 days; (b) BMX + PTH1-34 NH ₂ for 21 days + calcitonin for 22-84 days (C) BMX + PTH1-34 NH ₂ for 21 days + alendronic acid for 22-84 days; and (d) BMX + PTH1-34 NH ₂ for 1-84 days; FIG. 7B shows the results of using the same group of animals as in FIG. 7A using a micro-CT imaging technique that provides high resolution analysis of the bone marrow cavity of the femoral shaft.

Detailed Description of the Invention and Preferred Embodiments As pointed out in the discussion relating to the background of the invention above, the inventors have described, for example, bone tissue anabolic agents (eg, New bone tissue formed by the action of bone tissue augmenting agents (such as parathyroid hormone) is not natural in nature, and such bones are actually applied with certain anabolic treatments (alone) It was found that it was at least partially reabsorbed. To address this problem, the inventors have described two different approaches for preserving new bone tissue in the bone marrow cavity that lacks cancellous bone “scaffolds”. It can act as a scaffold to assist in nurturing the growth or maintenance of new bone tissue, such as the action of resorption inhibitors such as bisphosphonates (for example, The input of one or more biocompatible substances is (but is not limited to).

  For the purpose of simplifying the description of the present invention, in accordance with the present invention, a substance for forming a scaffold to promote bone tissue growth in the target bone tissue is generally referred to below as “ It is referred to as “biocompatible material” and / or “biologically active material”. In the following, this term is not only bone cement (biocompatible bone cement) but also other substances such as polymers, gels and / or those currently known or found in the future, such as calcium phosphate or hydroxyapatite. Or also include foams, slurries or suspensions, which provide the ability to form the necessary scaffolds in the internal parts of the bone.

  In addition, mechanically cause an increase in cellular activity, eg via bone marrow irrigation, and an increase in bone tissue such as bone tissue anabolic agents where there is a sufficient amount of cancellous bone to provide a scaffolding effect Combining the administration of agents has been found to be sufficient to maintain bone tissue growth during treatment with anabolic agents. However, it is biocompatible at sites that lack trabecular microstructure (see, eg, FIGS. 1A and 1B), or at sites that are at risk and / or where many trabeculae are perforated. The introduction of sexual substances—in combination with bone marrow irrigation and treatment with anabolic agents as described above—increased overall bone assimilation and maintenance. Bone tissue resorption in long bone shafts, lacking cancellous bone structure, e.g. increased bone anabolic agents, increased osteoblast activity in bone tissue targeted for additional bone tissue growth It has also been observed that it occurs when administered with the induction of This technique is described, for example, in US Patent No. 11 / 128,095 filed May 11, 2005 and US Patent No. 11 / 267,987 filed November 7, 2005, which is incorporated herein by reference. Incorporated by

  As shown in FIG. 1A, a 24-hour treatment of PTH expands the bone tissue-forming layer, which follows BMX and leads to the formation of additional bone tissue. On day 84, bone tissue reconstitution is performed, which causes the resorption of a substantial portion of the bone seen on day 21 of the BMX and BMX + PTH groups. This result suggests that resorption occurs gradually in areas of bone tissue that lack the cancellous bone network (eg, scaffold).

  Considering FIG. 1B, it can be seen that as a result of day 21 of BMX, there is a large amount of newly formed bone tissue in the medullary canal, which is further increased by a 24 day prescription of PTH. In contrast, the bone marrow of the central diaphysis of BMX-treated femurs taken from rats administered with PBS or PTH for 84 days no longer undergoes bone tissue formation, and in fact no more substantial bone tissue. Contains no amount. These results are confirmed from the observations labeled with calcein, as shown in FIG. 1A.

  As indicated above, the methods and compositions according to the present invention provide that bone tissue resorption is delayed and / or reduced by administration of resorption inhibitors such as calcitonin and / or alendronate. As will be achieved, to the extent possible, even if the lack of all bone tissue cannot be removed, it is preferred for obvious reasons, and the present invention is long bone, buttocks Useful in the spine and, in fact, in bone tissue lacking the cancellous bone network (or reduced). Accordingly, the present invention provides methods and compositions for achieving rapid and sustained growth of targeted bone tissue, which at the same time allows the new bone tissue produced in this way to identify bone tissue. In conjunction with a favorable reduction in the absence due to factors such as reabsorption at the targeted location.

  In one embodiment, as shown at 100 in FIG. 2, the present invention shows a method for augmenting bone tissue, which is solid, such as the femur or humerus Including but not limited to long bones and long bones such as vertebrae. As used herein, “increase” or “increasing agent” means an increase in the amount and / or density of bone tissue contained within the bone tissue, which is newly produced by use of the present invention. This corresponds to reducing or preventing the subsequent accelerated resorption of the bone tissue as completely as possible.

  The above is accomplished in one step by the use of a method comprising providing a biologically active substance such as bone cement inside the bone tissue to be increased. Biocompatible materials, including but not limited to bone cement, are brought about through radiographically controlled methods or laparotomy. Various biocompatible materials that are effective for use in the methods of the present invention are described in more detail below.

  Biologically active substances are associated with cancellous bone structures that are present in a portion of the targeted bone tissue, such as where the fracture occurred or the risk of future fractures due to reduced bone density To restore normal bone tissue function and strength at a desired location, such as a sexual location, a scaffold is formed that serves as a skeleton that allows the formation of additional bone tissue. Gradually, in the presence of anabolic agents, cement and newly formed bone tissue are dissolved into existing bone structure. This is advantageous in that normal trabeculae have fine weight distribution, compression shear strength and regeneration properties that cannot be regenerated, for example, when bone cement is used alone.

  In this discussion, the increase in vertebrae is often used as an illustration of the present invention. However, the present invention is not to be construed as limited to the use of vertebrae only. That is, as described above, including, but not limited to, other bones such as buttocks, distal femoral neck, distal radius, proximal humerus, radius, radius, tibia and sacrum Such other bones are increased by the methods shown herein.

  Referring now to FIG. 3 of the present application, the spine is generally indicated at 50. Vertebral bone 50 has an osteoporotic fracture or spinal malformation and further illustrates one type of bone tissue and a corresponding condition that can be treated by use of method 100 (eg, a fracture). In order to treat vertebra 50 with method 100 in this manner, step 110 is performed, which involves administering a biologically active substance after irrigation to remove stromal cells. Including. In some cases, the introduction of a biocompatible substance into the bone tissue may serve as a method for removing stromal cells, but a more preferred method is sufficient to remove stromal cell bone marrow. Includes pre-treatment of irrigation to remove.

  In the case of a vertebra such as vertebra 50, administration of the biocompatible material is typically performed by vertebroplasty or vertebral osteoplasty. In FIG. 2, the vertebra 50 has undergone vertebroplasty because of the effect of step 110. This figure therefore shows that a vertebroplasty needle 54 has been inserted by a transpedicular approach and the tip of the needle 54 is located inside the vertebral body 58. Stromal cell irrigation and removal is accomplished with a modified special needle that provides a better method for irrigation and collection of the same needle or stromal cells.

  It is understood that the execution of step 110 on the vertebrae 50 is effected using known or anticipated vertebroplasty techniques, which use the appropriate desired needle, image guidance modality, and the like. . The type of biocompatible material (eg, bone cement) 62 will be selected as a means of influencing such options and complementing the options used to produce the effects of step 120.

  As another way to perform the method 100, administration of biocompatible substance and augmenting agent can also be achieved by injection into separate vertebral bodies. Thus, the cement or biocompatible matrix material is injected into one of the vertebral pedicles, and the bone tissue augmenting agent is the other pedicle or the same pedicle as the biocompatible one. Through, can be injected through the ipsilateral approach, or mixed there instead. An anabolic agent is administered systemically as well.

In the methods of the present invention shown herein, a biocompatible material means, in one embodiment of the present invention, at least one bone cement, which in this specification is biological. Active bone cement is also described. Suitable biocompatible materials include, but are not limited to, calcium phosphate, calcium hydroxyapatite, calcium sulfate, calcium aluminate, bone morphogenic protein, polymer, fibrinogen, synthetic fibrin, collagen gel, collagen + hydroxy Including apatite suspensions and various combinations thereof. Specific illustrations of these materials are provided for the purpose of illustrating the invention only (and are not limited thereto): (a) Alpha-BSM bone replacement materials, bone tissue crystals Contains the biologically resorbable alternatives whose structural chemical composition and crystal structure are designed and sold by ETEX Corporation, Cambridge Massachusetts; (b) Cortoss synthetic cortical bone, two functions Sold by Orthovita Corp., Malverne Pennsylvania, provided by two pastes that are mixed on demand with (c) cementite LV, non-stoichiometric hydroxyapatite, present in aqueous solution Prepared by Teknimid lacated at 65500 VIC en Bigorre, France, prepared by reaction between acid and base of calcium phosphate under; Pepgen P-15, a high purity inanimate bovine transplant material, peptide-enhanced to reproduce radiopaque, autogenic bone tissue, Dentsply
Sold by Friadent CereaMed Lakewood COP-P; and (e) Norian SRS (Skeletal Repair System), injectable, moldable and biocompatible calcium phosphate, apatite carbonate at body temperature Fixed at, Synthes, Inc. located in West Chester, sold by Pennsylvania.

  For example, select a combination where one or more cements provide short-term stability and / or pain relief while others provide long-term integration and formation of new bone tissue This is considered desirable. The selection of biocompatible materials will be site specific. For example, the biocompatible material used to prevent hip fractures will be different from the biological material used to reinforce the vertebra during vertebroplasty. Furthermore, in most cases, biocompatible materials will not be used readily available. This is such that its formulation and / or physical state can be changed as needed for a particular application, for example it can be converted into a suspension, foaming agent or gel and / or contain these substances This is done by changing factors such as solid particle concentration, size, and shape.

  Improved bone cement is also useful in the present invention and further comprises bone cement and an augmenting agent. Examples of bone cements used in such improved bone cements include Cementtech and Cementtech LV, while examples of augmenting agents used in these improved bone cements include insulin-related growth factors. ("IGF"), rhPTH, GH, anabolic vitamin D analog, low density riboprotein receptor related protein 5 (LRP5) activator, or sclerostin LRP5 binding inhibitor, nongenomic estrogen signal activator (ANGELS), bone tissue Morphogenic protein, growth hormone related factor (GHRF), stem cell growth factor (HGF), calcitonin gene related peptide (CGRP), parathyroid hormone related peptide (PTHrP), transforming growth factor (TGF) and / or combinations thereof Including.

  In accordance with the present invention, the embodiments described herein may constitute further steps (eg, in conjunction with introducing biologically active bone cement into the targeted bone tissue). Which may include administering a bone tissue anabolic agent to the patient. It is envisioned that the bone tissue anabolic agent is administered to the patient daily, for example for up to 6 months. For example, an augmenting agent such as a bone tissue anabolic composition promotes trabecular growth on the surface of the scaffold formed by bone cement, at least compared to methods using either bone cement or bone tissue augmenting agent. Or otherwise by strengthening and subsequently resulting in a decrease in bone tissue resorption. The bone augmenting agent can be administered in any suitable manner, which can be injection, intravenous (“IV”), oral (“PO”), transdermal, nasal or enteral, and bone tissue Including the appropriate time during or after the introduction of bone cement into the interior of the.

  As described above, for example, according to the description, for example, for transdermal and nasal administration, the drug can be administered systemically or directly to the site where the bone cement is introduced. The timing and method of administration of the bone tissue augmenting agent is well understood by those skilled in the art. That is, the steps of method 100 can be performed in a different order than shown, or can be performed simultaneously. The bone tissue augmentation agent can be a bone tissue anabolic agent or other agent that promotes the penetration of injected cement, as described above. As indicated above, bone tissue augmentation agents have been found to produce a binding effect with that provided by bone cement. And bone cement helps to convert biologically active bone cement into actual bone tissue more quickly than is usually achieved by poor quality trabeculae of osteoporotic patients. In the absence of bone tissue anabolic agents, bone cement can be resorbed and reduce its effectiveness. Some useful bone tissue augmenting agents are exemplified below.

In a particular embodiment as illustrated in FIG. 4, a sufficient amount of one preferred bone tissue anabolic agent is administered to patient 68, eg, PTH [1-34] NH ₂ , eg, by needle 72, and the patient It is achieved that the pulsating blood concentration in is maintained between about 50 to about 350 pg / ml, preferably about 100 to 200 pg / ml, and most preferably about 150 pg / ml. In other embodiments, the patient's blood concentration of PTH [1-34] NH ₂ increases to a preferred level within 7 days of performing step 110. As is well understood by those skilled in the art, the appropriate PTH [1-34] NH ₂ is determined to achieve the desired blood concentration. When injecting the composition through a needle, although not necessary, the dosage ranges between about 10 to about 200 micrograms (“μg”) per day, more preferably from about 20 to about 20 per dose. It may be between about 100 μg, and more preferably between about 20 to about 50 μg per dose, or more preferably between about 20 to 40 μg per daily dose. Furthermore, as is well understood by those skilled in the art, the dosage level of an injectable formulation comprising a bone tissue augmenting agent other than PTH [1-34] NH ₂ is described in detail below. Consistent with what is described in the specification. If desired, PTH [1-34] OH can also be used in the same manner as described above.

Alternative methods for performing the method 100 are additionally intended to be within the scope of the present invention. Referring now to FIG. 5, the vertebra is generally designated 50a. The vertebra 50a also has an osteoporotic fracture and illustrates one bone tissue type (vertebra) and the corresponding condition (fracture) that can be treated using the method 100. However, in the present embodiment, method 100, step 110 and step 120 used to treat vertebra 50a are performed substantially simultaneously. FIG. 5 shows an improved or derivatized bone cement 62a. In FIG. 2, a vertebroplasty needle 54a is inserted according to a transpedicular, and the tip of the needle 54a is located inside the vertebral body 58a. Needle 54a also shows squeezing improved bone cement 62a into vertebral body 58a.

  An example of one embodiment shown herein includes a method of treating osteoporotic fractures in an individual's body in need of treatment for osteoporotic fractures, wherein the biologically active bone cement (Hereinafter also referred to as “biological material”) is brought into the bone tissue, and orally administered bone tissue augmentation agent is the same kind of material as normal natural bone tissue from when cement is injected. Is used to assist in promoting the growth of bone tissue on, in and / or around cement particles, and the additional bone tissue thus formed grows more rapidly And it is significantly less resorbed than methods in which bone tissue augmenting agents or cements are used alone.

  Other examples include methods of treating osteoporotic fractures in the body of an individual in need of treatment for osteoporotic fractures, where the biological material is delivered to the bone tissue and the augmenting agent is transnasally Is administered, which helps the biological material to be integrated and converted from the injected state into a material homologous to normal natural bone tissue as described above. Yet another example embodiment includes a method of treating osteoporotic fractures in an individual's body in need of treatment for osteoporotic fractures, wherein the biological material is delivered to the bone tissue. The bulking and augmenting agent is administered transdermally, which helps the biological material to be integrated and converted from the injected state into a material similar to normal natural bone.

  A further example includes a method of treating osteoporotic fractures in an individual's body in need of treatment for osteoporotic fractures, wherein biological material is brought into the bone tissue and injected The augmenting agent assists in its integration and conversion from the injected state into a substance similar to normal natural bone tissue.

  Furthermore, an example of this embodiment includes a method of treating osteoporotic fractures in the body of an individual in need of treatment for osteoporotic fractures, wherein biological material is provided to the bone tissue, and Parathyroid hormone ("PTH") assists in the integration and conversion of biological material from the injected form into a material similar to normal natural bone tissue.

  Another example includes a method of treating osteoporotic fractures in the body of an individual in need of treatment for osteoporotic fractures, wherein the biological material is brought inside the bone tissue and the recombinant accessory Thyroid hormone (“rhPTH”) assists in the integration and conversion from the state in which it is injected into the same type of material as normal natural bone tissue.

  A further example of an embodiment of the present invention includes a method for treating osteoporotic fractures in the body of an individual in need of treatment for osteoporotic fractures, wherein the biological material is contained within the bone tissue. And helps calcitonin be integrated and converted from its injected state into a material similar to normal natural bone tissue.

  Yet another example of an embodiment includes a method of treating an osteoporotic fracture in an individual's bone that requires treatment of an osteoporotic fracture, wherein the biological material is transported into the bone tissue. It helps the growth hormone be integrated and converted from its injected state into a substance similar to normal natural bone tissue.

Another additional example includes a method of treating osteoporotic fractures in the body of an individual in need of treatment of osteoporotic fractures, wherein biological material is brought into the bone tissue and Insulin-related growth factor assists in the integration and conversion from the injected state into a substance similar to normal natural bone tissue. A further example includes a method of treatment of osteoporotic fractures in the body of an individual in need of treatment of osteoporotic fractures, wherein bone cement consisting of calcium phosphate is brought into the bone tissue and integrated stimulation It helps the agent be integrated and converted from the state it was injected into to the same kind of material as normal natural bone tissue.

  Another example includes a method for treating osteoporotic fractures in the body of an individual in need of treatment for osteoporotic fractures, wherein the bone cement is made of calcium hydroxyapatite and brought into the bone tissue, And integrative stimulants help it be integrated and converted from the injected state to substances of the same nature as normal natural bone tissue.

  Yet another example includes a method of treating osteoporotic fractures in the body of an individual in need of treatment for osteoporotic fractures, wherein bone cement comprising calcium phosphate is brought into the bone tissue and An integrative stimulant assists in the integration and conversion from the injected state into a substance similar to normal natural bone tissue.

  Another example includes a method for treating osteoporotic fractures in the body of an individual in need of treatment for osteoporotic fractures, wherein bone cement made of calcium aluminate is brought into the bone tissue, And integrative stimulants help it be integrated and converted from the injected state to substances of the same nature as normal natural bone tissue.

  A further example of this embodiment includes a method for treating osteoporotic fractures in the body of an individual in need of treatment for osteoporotic fractures, wherein the bone cement comprising bone morphogenetic protein is contained within the bone tissue. And integrative stimulants help it be integrated and converted from the injected state to a substance similar to normal natural bone tissue.

  Another example includes a method of treating a vertebral fracture in an individual in need of treatment of a vertebral fracture, wherein it uses a cement in which insulin-related growth factor (“IGF”) is incorporated, which is delivered to the vertebrae. This method further includes using calcitonin or PTH or other bone tissue growth promoter using any suitable method of administration, for example, oral, nasal, injection, transdermal.

  Yet another example includes a method of treating osteoporotic fractures in the body of an individual in need of treatment for osteoporotic fractures, wherein biological material is brought into the bone tissue and further modified Thyroid hormone (“rhPTH”) is also brought into the bone tissue along with the cement, which is integrated into the same kind of material as normal natural bone tissue from the local bone tissue growth and cement injection state and Acts as a promoter of being converted.

  Further, an example of an embodiment of the present invention includes a method for treating osteoporotic fractures in the body of an individual in need of treatment for osteoporotic fractures, wherein the biological material is contained within the bone tissue. In addition, recombinant parathyroid hormone (“rhPTH”) and insulin-related growth factors are introduced into the bone tissue along with the cement, from the local bone tissue growth and from the state in which the cement is injected, to normal natural bone tissue. It is provided as an accelerator for the integration and conversion of similar substances.

  Another example includes a method of treating osteoporotic fractures in the body of a patient in need of treatment for osteoporotic fractures, wherein the biological material is brought inside the bone tissue and the recombinant parathyroid gland Hormones (“rhPTH”) and insulin-related growth factors are also integrated and converted into bone tissue, together with cement, from local bone growth and cement-injected materials to the same materials as normal natural bone tissue As an accelerator. At the same time, systemic bone tissue growth promoters by oral / IV or other methods are provided for a wide increase in a wide range of bone densities.

  The above-described examples of the present invention can include further steps that alter the contents of the bone marrow cavity inside the bone tissue in response to removing all or part of the stromal cells from the cavity. That is. Administration of biocompatible substances can achieve this goal by removing cells from the bone marrow cavity, or other methods such as irrigation are alternatively used for the same purpose.

  For example, as shown in FIG. 6A, the results of the formation of bone tissue in the femoral bone that was subjected to biocompatible matrix material and subsequently treated with PTH was significantly better than that of buffer alone (PBS) alone. It is. This result indicates that using BMX in combination with a biocompatible matrix fosters continuous bone tissue growth and additional PTH further improves this response.

As further shown in FIG. 6B, either BMX + PTH1-34NH ₂ and the biocompatible material gave better results than using only the biocompatible material after BMX. This result is confirmed by the observations obtained using calcein labeling as shown in FIG. 1A.

  FIG. 7A shows bone tissue formed in the bone marrow cavity in response to bone marrow removal (BMX) followed by 21 days of PTH treatment, which is followed by 63 days of calcitonin or alendron. Protected by acid treatment, which is represented by the fluorescent signal from calcein incorporated into the petrified bone. Alendronate was a potent resorption inhibitor and had excellent protective effects on newly synthesized bone tissue at the doses administered. In contrast, the removed bone marrow cavity of the femur from rats treated with PTH for 84 days has a minimal fluorescent label. Calcein was injected 9, 8, 2 and 1 day before animal sacrifice.

  In addition, calcitonin and alendronate protect bone tissue formation in response to bone marrow removal (BMX) and 21 days of PTH treatment. As shown in FIG. 7A, the formation of bone tissue in the bone marrow cavity in response to bone marrow removal and subsequent treatment with 21 days of PTH was protected by the next 63 days of administration of calcitonin or alendronate, which was petrified. Represented by the fluorescent signal from calcein incorporated into the bone. In contrast, the removed bone marrow cavity of the femur of a rat that received 84 days of PTH treatment no longer contains a fluorescent label.

  In addition, FIG. 7B shows bone marrow in response to bone marrow removal followed by 21 days of PTH treatment followed by continued treatment with either the reabsorption inhibitor calcitonin or alendronate for an additional 63 days. The result of the micro-CT analysis of the bone tissue formed in the cavity is shown. Calcitonin, and in particular alendronate, protects bone tissue formed in response to bone marrow removal and 21 days of treatment with PTH. In contrast, the removed bone marrow cavity of the femoral shaft of a rat treated with PTH for 84 days no longer contains bone tissue that appears dark on X-rays. This result confirms that in an anatomical region lacking a trabecular spongy network, continuous PTH treatment results in bone tissue resorption. However, administration of bisphosphonates can protect newly formed bone tissue in such locations.

  In a preferred embodiment, the method of the invention is also used for humans. However, the invention further includes applications in the field of veterinary medicine.

As a further alternative to the embodiments described so far, the present invention includes the additional step of mechanically inducing increasing osteoblast activity in the patient to be treated, said induction as described above. In addition, a biocompatible substance such as bone cement is added to the bone, and a bone tissue increasing agent such as a bone tissue anabolic agent is administered. The various steps can be performed in any order, but close enough in time, that is, an elevated concentration of at least one increasing agent in the patient's bloodstream and a mechanically induced elevated osteoblast in the patient. Cell activity is at least partially overlapping. Administration of the resorption inhibitor to the patient at any step is performed for a period and at a concentration sufficient to further reduce resorption of bone tissue formed by the synergistic relationship of the various method steps. Additional factors that avoid resorption and storage of additional bone tissue growth achieved through the method of the present invention include the presence of bone cement. It also serves as a scaffold or aid to help spread and grow from there. Once a sufficient amount of bone tissue has been formed, the resorption inhibitor is administered to protect the constructed bone tissue.

  Mechanical guidance is not essential, but uses a method that involves mechanically changing the contents of the bone marrow cavity that is internal to the bone tissue and where growth and protection of additional bone tissue growth is desired. Achieved. Methods for accomplishing varying the contents of various such bone marrow cavities are set forth below.

  Induction of bone tissue growth may, for example, produce new or additional bone tissue in locations where bone tissue growth is not currently occurring, and / or stimulate growth of bone tissue that is already being formed (eg, , Increase speed). Without being bound in any way by theory, Applicants have found that induction of bone tissue growth is (1) mechanical induction of osteoblast activity in the treated patient and (2) at least one bone tissue assimilation in the patient. I believe that this is caused by the combined effect of increasing the blood concentration of the drug. Throughout this specification, what is shown as bone tissue formed by the process of the present invention is not limited to trabecular bone, but includes one or more of the following additional bone “types”: Bone, cortical bone and / or lamellar bone.

  In a preferred embodiment of the invention, the mechanical induction of increased osteoblast activity is obtained by a bone marrow irrigation and removal process. Again, without being bound by any theory, Applicants have found that bone marrow irrigation or mechanical processes lead to thrombus formation in the bone marrow cavity through a cascade of biochemical reactions, which leads to osteoblast activity in the patient. I believe it will contribute to the rise.

  In other embodiments, elevated osteoblast activity can alternatively be obtained by combining other additional forms of induction, such as mechanical induction and biochemical induction. Such biochemical induction may be obtained, for example, by administering to a patient a sufficient amount of blood factor of Factor 7 (“F”), fibrinogen or fibrin, Factor VIIa or combinations thereof. Following tissue or vascular trauma, clotting is caused by the binding of crystalline FVII / FVIIa and tissue factor (tissue thromboplastin). This complex (FVII / FVIIa + thromboplastin) causes a series of events that lead to the activation of the coagulation cascade and ultimately to fibrin precipitation and platelet activation. Successive events with this complex will contribute in part to the stimulation of osteoblasts within the bone marrow. Factor VII and Factor VIIa are commercially available forms, for example, marketed by Novonoldix.

The increase in osteoblast activity obtained by the use of the method of the present invention may be caused by various factors including but not necessarily limited to: (1) Osteoblast differentiation, eg Production of additional osteoblasts, (2) increased osteoblast activity and / or effectiveness already present in inducing the formation of bone tissue in the patient, and (3) combinations thereof. In a preferred embodiment of the invention, the increase in osteoblast activity can include all the above functions.

  In one embodiment of the invention, the method further includes “targeting” one or more specified bone tissues of the patient for bone tissue guidance. This targeting is accomplished by inducing mechanical changes in the contents of the bone marrow cavity in each targeted bone tissue to increase osteoblast activity therein.

  The method of the present invention is thus not only useful for bone tissue repair, eg, in the case of trauma fractures, but also by dual energy X-ray absorption measurement (“DEXA”) or other In individuals whose methods have been shown to require increased bone mass and / or density (eg, those suffering from osteoporosis) to prevent fractures, or symptoms such as spinal compression It is also useful for strengthening bone tissue in a specific way in the case of individuals whose bone tissue is weakened by chronic pain due to. In addition, the method of the present invention provides for the provision of new bone tissue that needs to act as an anchor for implants such as, for example, prosthetic hip joints, artificial knees and shoulder joints, and / or dental implants (and Hold). New bone tissue growth can target bone tissue at risk of fracture, thereby reducing the risk of fracture.

  In one embodiment of the invention, the bone tissue anabolic agent is caused by mechanical induction of osteoblast activity (increased osteoblast formation and / or increased bone tissue formation by existing osteoblasts). ), Administered to the patient at the same time. The mechanical guidance is achieved, for example, by changing the bone marrow cavity. In preferred embodiments, the contents of the medulla and / or medullary cavity are under pressure (eg, by changing the associated pressure inside the medullary cavity versus outside the medullary cavity), for example, irrigating the medullary cavity and removing substrate cells Is removed.

  In other embodiments, the bone tissue anabolic agent is administered following such mechanical induction. In other embodiments, the bone tissue anabolic agent is administered prior to mechanical induction, and at the time of mechanical induction the bone tissue anabolic agent is already present at an elevated level, which level is then maintained for an extended period of time. Or it can be continued intermittently.

As shown in the above discussion, bone tissue anabolic agents are oral, intravenous, intramuscular, subcutaneous, implant, transmucosal, transdermal, enteral, nasal, accumulation It can be administered by injection or inhalation and pulmonary absorption. In other embodiments, the bone tissue anabolic agent can be administered as a sustained release agent once, multiple times, or over one or more long periods. Preferably, the elevated blood concentration of the anabolic agent is maintained at least intermittently for about 14-365 days, more preferably about 30-180 days after mechanical induction. Intermittent administration of parathyroid hormone, eg, PTH [1-34] -NH ₂ , causes a peak blood concentration once a day or once a week, which is baseline during each administration Back to the level but nevertheless results in a periodic increase in the blood level of the bone tissue anabolic agent, which overlaps with the initially mechanically induced increase in osteoblast activity, however, At least a portion of the increase in osteoblast activity is then maintained by the anabolic agent.

In additional embodiments, the anabolic agent is parathyroid hormone (PTH), an anabolic vitamin D analog, a low density lipoprotein receptor-related protein activator 5 (LRP5), or a sclerostin LRP5 binding inhibitor, a non-genomic estrogen-like signal. Transfer activator (ANGELS), bone morphogenetic protein (BMP), insulin-like growth growth factor (IGF), fibroblast growth factor (FGF), leptin, prostaglandin, statin, 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 Choose from a group of combinations It is. The term parathyroid hormone here is not limited, but includes natural parathyroid hormone, natural parathyroid hormone cleavage products, amidated natural parathyroid hormone cleavage products, amidated natural parathyroid hormone, and These combinations are included.

In one embodiment, the bone tissue anabolic agent is the free acid form of the PTH [1-34] cleavage product. This material is commercially available from Eli Lilly under the trade name Forteo® (Teriparatide) as a FDA approved pharmaceutical formulation. Other bone tissue anabolic agents useful for use in the present invention include, but are not limited to, amidated natural parathyroid hormone cleavage products, PTH [1-30] NH ₂ , PTH [1-31]. NH _2, including _{PTH [1-32] NH 2, PTH} [1-33] NH 2, PTH [1-34] NH 2 and combinations thereof. In one preferred embodiment, the bone anabolic agent is PTH [1-34] NH _2. A method for preparing parathyroid hormone cleavage products is described in US Pat. No. 6,103,495 to Mehta et al. In addition, methods for amidation of these parathyroid hormone cleavage products are described, for example, in Bertelsen et al. US Pat. No. 5,789,234 and Gilligan et al. 6,319,685. The contents of these patents are incorporated herein by reference.

  In one embodiment of the invention, a sufficient amount of a preferred parathyroid hormone cleavage product (see discussion above) has a pulsating blood concentration in the patient of about 50 to 350 pg / ml, preferably about 100 to 200 pg / ml, And most preferably administered to achieve and subsequently maintain about 150 pg / ml. In other embodiments, the blood concentration of parathyroid hormone in a patient rises to a preferred level within 7 days after mechanical changes in the contents of the bone marrow cavity. As is well known in the art, an appropriate volume of PTH bone tissue anabolic agent should be calculated to achieve the above blood concentrations. In the case of injectable dosage forms, for example, the volume to be administered to a human (pure amount of activating hormone) is noted in the literature relating to the bone tissue anabolic effects of these various agents. Such a volume, if administered by parenteral route, is not necessarily about 10-200 μg, once a day, more preferably about 20-100 μg, and most preferably The single dose is about 20-50 μg. The dosage level of injectable dosage forms containing bone tissue anabolic agents other than the parathyroid hormone-based agents described above is consistent with the known blood levels required to cause anabolic effects depending on the human. Would have done.

  In a further embodiment of the present invention, the mechanical induction of osteoblast activity is to physically move the contents of the medullary cavity into the bone marrow cavity of the targeted bone tissue for enhanced bone tissue formation. This is accomplished by inserting something adapted or adapted to change and stimulating osteoblast activity in the medullary canal. In other embodiments, the mechanical change includes removing at least a portion of the contents in the medullary canal. A suitable method is to irrigate the bone marrow cavity with solution to remove matrix cells. In certain embodiments, a biocompatible material is used to remove bone marrow cells and induce osteoblast activity.

  In a further embodiment, the method of the invention further provides the patient with a resorption inhibitor at a sufficient period of time and at a concentration sufficient to substantially prevent resorption of new bone tissue produced by osteoblast activity. Administration. In one embodiment, the resorption inhibitor can be administered contemporaneously with the bone tissue anabolic agent. In one embodiment, the resorption inhibitor may be administered following administration of the bone tissue anabolic agent. In further embodiments, administration of the resorption inhibitor is initiated during administration of the bone tissue anabolic agent, and the administration can continue after the administration of the bone tissue anabolic agent is terminated.

  In other embodiments of the present invention, one agent having both bone tissue anabolic and resorption inhibition properties can be administered. Examples of such substances include, but are not limited to, estrogen, strontium ranelate and selective estrogen receptor modulators (SERMS).

  In one embodiment of the method of the present invention, the reabsorption inhibitor comprises human calcitonin, salmon calcitonin (“sCT”), eel calcitonin, elcatonin, porcine calcitonin, chicken calcitonin, calcitonin gene related peptide (CGRP), and these It can be a calcitonin selected from the group comprising the combination. In a preferred embodiment, the resorption inhibitor is salmon calcitonin. When used as a reabsorption inhibitor, the blood level of calcitonin is preferably in the range of about 5-500 pg / ml, more preferably in the range of about 10-250 pg / ml, and most preferably 20-50 pg / ml. It is a range. In addition, the level of human administration of calcitonin preparations required to achieve long-term blood levels, for example in injectable dosage forms, is described in the literature relating to the use of these substances as anabolic agents. It will be. Such a volume is, but need not be, about 5-20 μg administered once daily, more preferably about 5-50 μg and most preferably 8-20 μg of pure drug dose administered daily. If salmon calcitonin (sCT) is administered by other routes of administration, such as nasally or orally, a larger volume than described above may be required.

  Alternatively, various additional resorption inhibitors (eg, other than calcitonin) are useful in the methods of the invention. These generally include hormone replacement therapy (HRT) agents such as selective estrogen receptor modulators (SERMS), bisphosphinates, cathepsin-K inhibitors, strontium ranelate, and various of these Includes combinations. Examples of specific additional resorption inhibitors include, but are not limited to: (1) Wyeth's Premarin®, and estrogen as an active ingredient. Typical acceptable volume is 0.625 mg tablet once a day; (2) Actron® from Procter & Gamble, Inc., containing risedronate sodium as active ingredient, typical acceptable volume is 1 mg 5 mg tablet Once a day or 35 mg tablets once a week; (3) Revista (registered trademark) manufactured by Eli Lilly and Raloxifene hydrochloride as an active ingredient. The typical tolerable capacity of this formulation is a 60 mg tablet once a day; and (4) Fossamax® from Merck and alendronic acid as the active ingredient. Typical volume of this substance is 10 mg / day or 70 mg / week. Additional bisphosphonates include Actonel® (Procter Gamble Aventis), Ibandronate® (GSK Roche) and Zorendronate® (Novaltis).

  Except where otherwise noted or apparent from the contents, the volumes described herein may be used for various excipients, diluents, carriers or other ingredients, typically various useful for the methods of the invention. The weight of the active ingredient which is not affected by the dosage form even if contained in the dosage form is shown. Any dosage form commonly used in the pharmaceutical industry (eg, capsules, tablets, injections or the like) is suitably used herein and is referred to as an “additive”, “diluent” or “ "Carrier" includes non-active ingredients as are typically included in the industry along with active ingredients. For example, typical capsules, pills, enteric coatings, solid or liquid diluents or additives, flavorings, preservatives, or the like. Furthermore, for all of the recommended volumes shown here, the attending physician should observe the individual patient's response and adjust the volume accordingly.

Reabsorption inhibitors are oral, vaporized, intramuscular, transdermal, through implant, transmucosal, enteral, nasal, through cumulative injection, through inhalant, and pulmonary absorption or transdermal Can be administered. Further, the resorption inhibitor may be administered once, many times, or over one or more long periods.

  Although the present invention has been described in connection with particular embodiments, many other variations and modifications and other uses will become apparent to those skilled in the art. The present invention is therefore not limited to the specific examples disclosed herein, but only by the claims.

Claims (31)

A method of increasing bone tissue in a patient with poor bone tissue, the method comprising:
(A) mechanically inducing increased osteoblast activity in said patient;
(B) Injecting a biocompatible substance in an amount sufficient to form a skeleton in the bone tissue within the bone tissue of the patient where osteoblast activity is induced. Wherein the skeleton serves to assist in the formation of new bone tissue in the interior portion; and (c) to increase the blood concentration of at least one bone tissue anabolic agent in the patient, Administering a sufficient amount of at least one bone tissue augmenting agent to the patient, wherein the increase in blood concentration of the anabolic agent in the patient and the increase in osteoblast activity at that time are at least partially Overlapping in time,
Including a method.   The biocompatible substance is selected from the group consisting of biologically active bone cement, bone morphogenetic protein, polymer, fibrinogen, synthetic fibrin, collagen gel, collagen including hydroxyapatite suspension, and combinations thereof. The method of claim 1, wherein:   The biocompatible material is a biologically active bone cement, and the bone cement is selected from the group consisting of calcium phosphate, calcium hydroxyapatite, calcium sulfate, and calcium aluminate. the method of.   The method according to claim 1, wherein the bone tissue increasing agent is a bone tissue anabolic agent.   The bone tissue anabolic agent is a parathyroid hormone (PTH), an anabolic vitamin D analog, a low density lipoprotein receptor-related protein 5 (LRP5) activator, or a sclerostin LRP5 binding inhibitor, a nongenomic estrogen-like signaling activator ( ANGELS), bone morphogenetic protein (BMP), insulin-like growth factor (IGF), fibroblast growth factor (FGF), leptin, prostaglandin, statin, strontium, growth hormone, growth hormone releasing factor (GHRF), liver The cell growth factor (HGF), calcitonin gene-related peptide (CGRP), parathyroid hormone-related peptide (PTHrP), transforming growth factor (TGF) -β1, and combinations thereof, Method.   The bone tissue anabolic agent is parathyroid hormone, and the hormone is natural parathyroid hormone, natural parathyroid hormone cleavage product, amidated natural parathyroid hormone cleavage product, amidated natural parathyroid hormone and combinations thereof 6. The method of claim 5, wherein the method is selected from the group consisting of:   7. The method of claim 6, wherein a sufficient amount of parathyroid hormone is administered to the patient to achieve a pulsatile blood concentration of the parathyroid hormone in the patient in the range of about 50-350 pg / ml.   7. The method of claim 6, wherein the sufficient amount of parathyroid hormone is about 10 [mu] g-10 mg of pure PTH hormone per dose.   The method of claim 6, wherein the parathyroid hormone is administered by injection, and a sufficient amount of the parathyroid hormone is about 10-200 μg per dose.   The method of claim 6, wherein the bone tissue anabolic agent is the free acid form of PTH [1-34]. The bone tissue anabolic agent is an amidated natural parathyroid hormone cleavage product, and the cleavage products are PTH [1-30] NH ₂ , PTH [1-31] NH ₂ , PTH [1-32] NH _2. The method of claim 6, selected from the group consisting of: PTH [1-33] NH ₂ , PTH [1-34] NH _2, and combinations thereof.   The method of claim 1, wherein the bone tissue augmenting agent is at least one agent that results in increased levels of endogenous anabolic agents in the patient.   13. The method of claim 12, wherein the agent that results in increased expression of an endogenous bone tissue anabolic agent in the patient is selected from the group consisting of calcilytic agents and sclerostin antibodies.   The method of claim 1, further comprising administering a resorption inhibitor to the patient, wherein the resorption inhibitor is administered in an amount sufficient to substantially prevent resorption of the new bone tissue growth. Method.   The reabsorption inhibitor is bisphosphonate or human calcitonin, salmon calcitonin, eel calcitonin, elcatonin, porcine calcitonin, chicken calcitonin, calcitonin gene related peptide (CGRP) and combinations thereof, The method according to claim 14.   The reabsorption inhibitor is salmon calcitonin, and the salmon calcitonin is administered to the patient in an amount calculated to achieve a substantially continuous blood concentration between about 5-500 pg / ml; The method of claim 15.   17. The method of claim 16, wherein the amount of salmon calcitonin is about 5 μg to 5 mg as a pure weight of calcitonin per dose.   17. The method of claim 16, wherein the salmon calcitonin is administered by injection and the amount of salmon calcitonin is about 5 [mu] g-200 [mu] g per dose.   The bone tissue augmenting agent is parathyroid hormone, wherein the blood concentration of the parathyroid hormone in the patient increases to a level between about 50-350 pg / ml within 7 days after the mechanical induction. The method of claim 1.   The method of claim 1, further comprising forming an amount of additional bone tissue in the patient's jaw region sufficient to provide an anchor for a dental implant that is implanted within the jaw region.   Further, in order to allow a prosthesis to be securely fixed therein in the at least one targeted bone tissue in the targeted one or more bone tissue of the patient. The method of claim 1, comprising forming a sufficient amount of additional bone tissue.   Forming a sufficient amount of additional bone tissue in the patient to serve as a secure anchor for a gapable, adjustable insert secured to the additional bone tissue The method of claim 1 comprising: Further comprising targeting at least one vertebra of the patient for the formation of additional bone tissue, wherein the patient is substantially free from chronic pain from vertebral collapse The method of claim 1, wherein the bone tissue is added to the at least one vertebra.   The method of claim 1, wherein additional bone tissue is formed on the at least one vertebra of the patient by an amount sufficient to stabilize the at least one vertebra by strengthening it.   The biocompatible substance is administered by injection to a site selected from the group consisting of proximal femur, buttocks, distal radius, proximal humerus, radius, radius, tibia and sacrum. Item 2. The method according to Item 1.   2. The method of claim 1, wherein the bone tissue augmenting agent is administered by a method selected from the group consisting of oral, nasal, transdermal, rectal, subcutaneous and intravenous administration. For nurturing and preserving bone tissue growth within bone tissue that lacks a sufficient amount of trabecular scaffold to substantially prevent resorption of new bone tissue formed within the bone tissue A kit, said kit:
(A) at least one container having at least one biocompatible material applied to form an additional amount of scaffold within the bone tissue within the container;
(B) at least one container having therein a bone tissue augmenting agent; and (c) a mechanical change device comprising the contents of the bone marrow cavity of at least one targeted bone tissue. Something to change,
Including a kit.   28. The kit of claim 27, wherein the biocompatible substance is a biologically active bone cement.   28. The kit according to claim 27, wherein the bone tissue increasing agent is a bone tissue anabolic agent.   28. The kit of claim 27, further comprising at least one container having at least one resorption inhibitor.   28. The kit of claim 27, further comprising a drainage device for draining at least a portion of the contents of the bone marrow cavity.