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Bone degradation: Osteoporosis – Symptoms and causes

A Strategy for Preserving Bone During Chemotherapy

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by NCI Staff

In this image of a normal mouse bone, the red and green lines represent new bone. Exposure to chemotherapy and radiation leads to bone loss and increases the risk of osteoporosis and fractures.

Credit: Zhangting Yao, Washington University School of Medicine

A new study in mice suggests that a biological process known as cellular senescence, which can be induced by cancer treatments, may play a role in bone loss associated with chemotherapy and radiation.

Senescence occurs when a cell permanently stops dividing but does not die. Senescent cells release a variety of substances into their environments that may affect neighboring cells.

“Senescent cells release many molecules,” said Sheila Stewart, Ph.D., of the Washington University School of Medicine in St. Louis, who led the study. “We found that some of the molecules released by senescent cells drive bone loss in mice receiving chemotherapy.”

Specifically, molecular signals from chemotherapy-induced senescent cells disrupted a process known as bone remodeling, the researchers reported in Cancer Research on January 13. During bone remodeling, cells called osteoclasts dismantle old bone and cells called osteoblasts build new bone.

Normally, osteoblasts and osteoclasts work in concert. “But when the balance is disrupted [by signals from senescent cells], bone can become too thin,” said Dr. Stewart. Thinning bone can lead to osteoporosis, increasing the risk of fractures and bone pain. 

The researchers also showed that two investigational drugs could block molecular signals from senescent cells that disrupt bone remodeling in mice. This approach, the researchers noted, could be evaluated as a possible strategy for preventing chemotherapy-induced bone loss in patients.

“A Good First Step”

“The mouse study is a good first step in an important and understudied area of cancer research—that is, the complexities of cellular senescence,” said Jeffrey Hildesheim, Ph. D., of NCI’s Division of Cancer Biology, who was not involved in the study. 

Cellular senescence is a biological response to stress, such as an injury or DNA damage caused by chemotherapy. The response, which can stimulate or activate the immune system, is involved in biological processes ranging from normal development to the healing of wounds.

Senescence has long been thought of as a way that the body blocks damaged cells from proliferating and giving rise to tumors. “But the new findings add to growing evidence that senescence may actually have a broad range of biological effects—some good and some bad—especially when there is accumulation of senescent cells, as may be the case in patients undergoing chemotherapy or in those who are not healthy enough to get rid of these cells,” said Dr. Hildesheim.

The immune system normally eliminates senescent cells after they are no longer needed, Dr. Hildesheim explained. But this may change as the immune system becomes increasingly compromised in older individuals; in fact, the accumulation of senescent cells is a hallmark of aging.

“This study challenges the classical view that senescence is always a good thing while also contributing to our growing appreciation of its detrimental effects if they persist,” Dr. Hildesheim added, noting that the effects of cellular senescence may vary depending on the context in which it occurs.

Studying Bone Loss in Mice

Previous studies have demonstrated that senescence drives bone loss associated with aging, which has raised the possibility that senescence contributes to chemotherapy-induced bone loss, the study authors noted.

Although some treatments for breast and prostate cancer can alter the level of sex hormones and contribute to bone loss, there is evidence that treatment-related bone loss must be due to more than just the absence of hormones, Dr. Stewart noted.

For example, patients with cancer who receive chemotherapy and radiation lose much more bone than women with breast cancer who are treated with drugs called aromatase inhibitors, which eliminate estrogen, according to the researchers.

“In this study, we wanted to understand what causes bone loss beyond a lack of estrogen and whether we could do anything about it,” Dr. Stewart said. Senescent cells secrete numerous substances that researchers refer to collectively as SASP, or senescence-associated secretory phenotype.

To investigate the role that senescence and this condition might play in bone loss associated with chemotherapy, the researchers first treated mice with two commonly used chemotherapy drugs, doxorubicin and paclitaxel. Some mice also received radiation to a leg.

All three treatments induced the process of cellular senescence, and senescent cells were present in the bones of the mice, the researchers reported.

“Our results support the idea that chemotherapy-induced senescence and the biological effects of this process lead to increased activity by osteoclasts, which can lead to thinner or weaker bone,” said Dr. Stewart.

In light of this new potential mechanism of bone loss, the researchers explored possible strategies for preserving bone in mice. The investigators focused on a signaling pathway called p38MAPK-MK2, which they had previously shown regulates the expression of some of the proteins secreted by senescent cells.

This signaling pathway was active in the bone cells of mice treated with chemotherapy, Dr. Stewart and her colleagues determined. In additional studies in mice, they demonstrated that two investigational drugs that target proteins in this pathway could reverse bone loss.

“The p38MAPK-MK2 pathway is an important piece of the puzzle and can inform future studies aimed at identifying combination therapies to manage the multiple effects of chemotherapy more comprehensively, as we gain insights into the mechanisms involved and their impact not only on cancer cells but also on normal tissues,” said Dr. Hildesheim.

In general, he continued, the study results highlight the need for drug developers and clinicians to focus more broadly on the potential side effects of drugs, including chemotherapy-induced senescence and bone loss.

New Drugs Are Needed

The two investigational drugs tested in the current study are already in human clinical trials for diseases other than cancer. One of the drugs, which is being studied in patients with inflammatory diseases, inhibits the p38 MAPK protein; the other drug inhibits the MK2 protein and will be tested in patients with rheumatoid arthritis.

“These are oral medications, and they have relatively few side effects,” said Dr. Stewart. In 2018, her team reported that inhibiting the p38MAPK-MK2 pathway slowed the growth of a form of metastatic breast cancer in mice.

This finding, along with the new results, has raised the possibility of using the two drugs to kill metastatic cancer cells while also reducing chemotherapy-induced bone loss, Dr. Stewart noted.  

“We are excited about these inhibitors and the potential for them to have an anticancer effect while also potentially preventing bone loss,” she said. But she cautioned that the p38MAPK-MK2 pathway is likely to be just one of many signaling pathways that contribute to chemotherapy-induced bone loss.

New drugs for treating patients with cancer who experience bone loss are needed, Dr. Stewart continued, noting that the medications currently in use, including bisphosphonates and denosumab (Prolia or Xgeva), have side effects and may not be appropriate for children, whose bones are still growing.

When Dr. Stewart and her colleagues began their investigation, they were focused on “just trying to understand what was going on with bone loss at a basic level.” But she is now optimistic that their findings could one day benefit patients. “It’s not often that basic science takes a researcher this close to the clinic,” she said.

What happens to bones in space?

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Astronaut Leroy Chiao, Expedition 10 commander and NASA International Space Station (ISS) science officer, equipped with a bungee harness, exercises on the Treadmill Vibration Isolation System (TVIS) in the Zvezda Service Module of the ISS. April 10, 2005. (Credit: NASA)


One of the major obstacles to long-term space missions in the threat of severe bone loss in astronauts. In the microgravity environment of space, astronauts lose on average 1% to 2% of their bone mineral density every month. For a short-duration flight, bone loss is a fairly minor consequence.

On a long-duration space flight, such as those planned for missions to Mars and beyond, bone loss can be a serious impediment. This loss may not hinder astronauts while they are in orbit, but upon return to Earth, their weakened bones will be fragile and at an increased risk of fractures. At this time, it is unknown whether this bone loss will eventually reach a plateau, or whether it will continue indefinitely.

Bones are not unchanging calcium structures; they constantly reshape themselves in relation to the stress that is put on them. Just like muscles, if you don’t use your bones, they will weaken. Bone loss occurs in the weightless environment of space because bones no longer have to support the body against gravity. On Earth, gravity applies a constant mechanical load to the skeletal system, that causes healthy bones to maintain a certain density so that they are able to support the body.

The best way to build bone mass is by doing weight-bearing exercises such as walking, jogging, volleyball, and basketball. However, it is very difficult to duplicate weight-bearing exercise in a weightless environment. Astronauts must use restraints to strap themselves to a treadmill in order to create the necessary weight-bearing environment. Although this countermeasure slows the rate of bone loss, it does not eliminate the problem altogether.

Astronauts are not the only ones who must worry about bone loss. One and a half million Canadians suffer from osteoporosis, a disease that causes bones to lose density and strength. One in four women and one in eight men over the age of 50 have osteoporosis. Researchers hope that solving the problem of bone loss in space will also help to prevent and cure the disease on Earth.

The changes that take place in bones from osteoporosis are similar to the changes that take place in astronauts’ bones when they live in microgravity for long periods of time.


Related links

  • “Space Bones” – Science@NASA Article: Weightlessness sure looks like a lot of fun, but prolonged exposure to zero-G in space can have some negative side effects – like the weakening of human bones.
  • Osteoporosis Experiments in Orbit – from the Canadian Space Agency’s Space Life Sciences
  • Osteoporosis online – from the Osteoporosis Society of Canada
  • Exercising in space

Explore further

  • MARROW: Keeping bones healthy in space
  • Effects of space on the body
  • Exercising in space



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ATROPHY AND LACK OF BONE TISSUE

Before

After

Problem: bone atrophy

Bone atrophy is a decrease in the alveolar process of the jaw, which is characterized by a decrease in the length and width of the bone, as well as a rarefaction of bone tissue. Atrophy is an inevitable consequence of tooth loss, in some cases, jaw trauma, inflammatory, hereditary genetic or other diseases.

Everything is interconnected in our body – and the loss of even one tooth leads not only to the displacement of the entire dentition, but also to a noticeable decrease in the volume of bone tissue. Externally, bone atrophy is noticeable only when it is clearly manifested, when most of the teeth on both jaws are missing. In this case, facial asymmetry appears, the dental arch decreases in size, the lips and cheeks “sink” into the oral cavity, the corners of the lips fall, and the remaining teeth move along the dentition.

Causes of bone atrophy:

  • loss of teeth – bone atrophy occurs as a result of reduced load: if the roots of the teeth are missing, the bone cells do not receive proper pressure and cease to be saturated with nutrients. Over time, the soft layers of the bone dissolve, the bone becomes thin, the gum falls through;
  • inflammatory diseases of the oral cavity, periodontal disease, removed cysts, granulomas and other tumors,
  • jaw injuries,
  • anatomical structure of the jaw,
  • hereditary diseases,
  • age-related changes in the body.

Consequences of bone tissue atrophy:

  • changes in the aesthetic characteristics of the face, including premature aging, the appearance of wrinkles,
  • impaired chewing function and, as a result, the development of diseases of the gastrointestinal tract,
  • changes in speech,
  • 9001 7 offset remaining teeth, deterioration of their condition.

The main and most important consequence of bone tissue atrophy is the impossibility of classical implantation. An implant that replaces the root of a tooth cannot be fixed in a bone that is too short and narrow.

Opinion of a specialist

Opinion of a specialist

Igor Yurievich Malinovsky

Oral and maxillofacial surgeon, implantologist

Experience: more than 14 years

The problem of bone tissue atrophy – low or narrow al veolar crest, as well as porous bone (resorption) – today effectively solved in a variety of ways. You can resort to osteoplastic surgery, or install basal implants, which, due to their length, are installed in the deep layers of the bone and are not at risk of rejection or loss of stability due to bone deficiency.

Solutions to the problem

Possible solutions to the problem are increasing the volume of bone tissue, installing a removable denture or a permanent bridge, as well as using dental implant methods that involve restoring the dentition without a bone augmentation procedure.

Option 1: Express Dental Implantation is the most advanced dental restoration method that does not require bone augmentation. The method is used to restore from 3 zbuov. Implants of various lengths and shapes are selected, which have a fastening for reliable fixation in the bone tissue, while the abutment (the protruding part of the implant for fastening the crown) is part of a solid structure. If there is an acute shortage of bone, then the implants are installed in the deep layers of the bone tissue, including, at the discretion of the implantologist, the implants can be installed at an angle to distribute the load. In addition, the doctor selects implants individually for a certain bone size, creating a complex design like a jeweler. With express implantation, prostheses on implants are installed on the 3rd day, implants take root as quickly as possible, due to the restoration of chewing function and stimulation of the natural processes of bone tissue restoration. Thus, patients return to a normal lifestyle within a week after implantation, and not after six months or a year, as is the case with classical implantation and sinus lift. Read more>

Option 2: Sinus lift is an operation performed on the upper jaw to increase the length of the bone tissue. Two main approaches are possible: with the simultaneous installation of implants (closed sinus lift), as well as by replanting bone material, its complete engraftment, and only after the installation of artificial roots (open sinus lift). The operation of the sinus lift is possible due to the partial release of space for bone tissue by shifting the bottom of the maxillary sinus. During the operation, it is lifted through a hole in the bone tissue, and the free space is filled with synthetic bone material. Read more>

Option 3: Osteoplasty is a procedure that is usually performed to increase the width of the bone (in the lower jaw, the problem of lack of bone length is quite rare). As materials for increasing bone volume, synthetic compounds are used, either donor bone blocks (animal or human, borrowed from other bone structures), as well as own bone material isolated from the patient’s blood plasma using special equipment. The latter option is more preferable, since own cells are not perceived as a foreign body and take root as quickly as possible. Read more>

Option 4: Removable prosthetics is one of the possible options for restoring teeth in case of bone atrophy. Complete or partial removable dentures quite successfully replace the dentition, however, the patient will have to face a number of inconveniences: insufficient aesthetics, long addiction, possible speech disorders and inflammation of the gums caused by rubbing of the structure, and a short service life. In addition, removable prosthetics will not allow you to restore a decreasing bone – it will still not receive the proper load and will continue to decrease in size. Ultimately, this will lead to a violation of aesthetics: after all, the gum will decrease along with the bone tissue and a gap will form between it and the prosthesis. Read more>

Option 5: Dental bridges – are a series of dental crowns combined with each other, allow you to restore several lost teeth, using the patient’s living teeth or installed implants as a support. Like removable dentures, in the case of support on living teeth, they only aggravate the process of bone atrophy, since under the denture it will continue to decrease in size. Read more>

Other problems:

  • Maxillary sinus disease
  • Broken (chipped) tooth
  • Missing one tooth
  • Scattered absence of teeth
  • Aesthetic defect of the smile area
  • End defect
  • Full edentulous
  • Facial deformity and speech defects
  • Caries under the crown
  • Pulpitis
  • Broken dental bridge
  • Tetracycline teeth
  • Implant failed
  • Tooth mobility and periodontitis

Author of the article

Igor Yurievich Malinovsky

Maxillofacial surgeon, implantologist

Experience: more than 14 years

Reliable implant options for bone atrophy

CONTENTS

  1. Why jaw bone shrinks
  2. Does the whole bone atrophy
  3. What are the consequences of atrophy
  4. What are the options for solving the problem
  5. How to increase bone tissue
  6. Is it possible to perform implantation without bone grafting

A serious obstacle to the implantation of teeth in the upper jaw is atrophy of the bone tissue. Without receiving the prescribed load, the bone in the places of the extracted teeth gradually resolves. Its height decreases, and in the region of the bottom of the maxillary sinus it becomes so thinner that there is simply nowhere to implant conventional implants. In such cases, classical implantation is not possible.

Modern dentistry has overcome this shortcoming, and the patients of our AcademStom clinic have a lot of assistive technologies at their disposal: sinus lift, basal implantation and Zygoma zygomatic implants. These techniques allow you to restore the integrity of the dentition even in the complete absence of teeth.

In this article, we propose to consider the issues of bone atrophy that occur in all patients who have lost at least one tooth. How dangerous are they? Who is at risk? And is there a universal solution to keep bones from resorption? The answers to these and other questions are given by practicing implantologists of our clinic.

Why does the jaw bone shrink?

Thanks to nature’s ability to withstand enormous chewing loads, the human jaw functions perfectly. The bone does not wear out and, moreover, the daily load is the key to its normal existence.

Chewing in the bone stimulates blood flow at the capillary level. With the influx of blood, metabolic processes are activated, the bone receives enough nutrients. After the loss of a tooth, the load on the area of ​​\u200b\u200bbone tissue stops, the blood supply worsens. New bone cells grow extremely reluctantly.

Other causes of jaw tissue degradation:

  • Gradual replacement of bone with gum cells . Soft tissue grows faster, displacing hard bone.
  • Age-related metabolic disorders . Loss of teeth manifests itself mainly in adulthood, when a person has chronic diseases, problems with the heart and blood vessels, impaired blood circulation and metabolism.
  • Inflammatory periodontal disease . When tissues are infected, the ligaments that hold the root in the bone alveolus are destroyed, and the bone tissues themselves also suffer.
  • Trauma and surgery for tumors . When the jaw is injured, resorption processes are accelerated and can occur at any age.
  • Use of unevenly loaded prostheses . All removable and non-removable prostheses fall into this category. When they are worn, the load during chewing falls on soft tissues and abutment teeth, while the rest of the bone remains unloaded.

Also, atrophy, according to the doctors of our AcademStom clinic, can be hereditary. In families prone to caries, early loss of teeth is possible and, accordingly, bone atrophy at a younger age.

Does all bone atrophy?

After the extraction of teeth, all jaw bones undergo atrophic processes. However, in different places this process proceeds unevenly. The lower jaw degrades slowly and becomes thinner in thickness.

The areas of the alveolar ridge of the upper jaw are most susceptible to atrophy. Located in the area of ​​the bottom of the maxillary sinus in the lateral sections of the jaw, they very quickly become thinner in height. Therefore, the implantation of these areas is always associated with huge problems.

What are the consequences of atrophy?

The process of atrophy does not go unnoticed. In addition to the inability to implant or prosthetize a jaw with significant atrophy, there are a number of other problems:

  • Change in gingival relief . This is the first sign of bone resorption. On the upper jaw, the gum rises, on the lower – falls.
  • Deterioration of appearance . Every year a person with a large number of missing teeth will change appearance. The lips sink in, the skin above them becomes folded and wrinkled. Gradually, the cheeks are involved in the process. The face becomes asymmetrical, looks older.
  • Dental dysplasia . The remaining teeth in the jaw can move into the vacant space. This is fraught with a violation of the aesthetics of a smile and functional chewing disorders, as well as damage to healthy teeth.
  • Problems with diction . The absence of teeth and the gradual degradation of bone tissue do not contribute to particularly clear diction. A person has annoying speech disorders that bring great discomfort.
  • Small selection of prosthetic methods . With a very advanced process, in fact, you can only use “false jaws” – removable dentures that do not prevent further atrophy. They will break with enviable regularity and will have to be redone.

A person with atrophy does not have much choice in prosthetics. Any method other than implantation will only exacerbate the problem. And in the future, you will have to do bone augmentation.

What are the possible solutions to the problem?

To prevent atrophy, it is necessary to immediately replace the lost tooth, since changes in the bone tissue begin already 3-4 months after its removal. With single defects, prosthetics with an immediate prosthesis or implantation at the same time with the removal of a decayed tooth are possible.

If the restoration is not carried out immediately, the doctor may recommend the installation of a special membrane that will not allow the gums to grow too much. In a couple of months, the bone will grow and level, and then you definitely need to put on a prosthesis.

Unfortunately, it will not be possible to stop the process of bone resorption by simple prosthetics. The load when wearing removable and non-removable structures is transferred only to the supporting teeth and soft tissues, and the area without teeth remains insufficiently loaded. The processes of atrophy will continue, albeit at a less intense pace.

Over time, the bone and gum will sag in this area, which will lead to the play of the prosthesis. It will have to be redone. Therefore, if possible, it is better to choose implantation. The implant, in fact, is no different from the usual root in functional terms. The bone under it will experience the prescribed loads, and there will be no atrophy.

If implantation is not immediately possible, bone grafting is performed. This operation is called augmentation. There are many techniques developed by dentistry over the past century. Some of them turned out to be unnecessarily traumatic, and are currently used only for a very narrow range of indications.

Most commonly used bone augmentation methods:

  • sinus lift;
  • auto- and donor transplantation.

The choice in favor of one or another method is made by the attending physician based on the complexity of the clinical case.

How is bone tissue increased?

Bone graft is a traumatic procedure. In autotransplantation, tissue is taken from the ilium or parietal bone. A scar remains at the site of the fence. With a donor – a suitable donor transplant is used.

The transplant itself is done under anesthesia and takes several hours. It is very important that the operation is performed by an experienced doctor so that the likelihood of complications is minimized.

Considering the high traumatism, this procedure is used only in rare cases – when a large amount of tumor-affected bone tissue has been removed or their deficiency has arisen due to trauma.

Sinus Lift is the most popular bone augmentation procedure. There are two types: closed and open. In the first case, a small amount of osteoplastic substance is placed in the cavity under the bottom of the maxillary sinus created during the preparation of the implant site. In this case, it is possible to build up only 2-3 mm of bone.

Open sinus lift is a more traumatic operation. A hole is made in the jaw, the mucosa is exfoliated and rises in the region of the bottom of the maxillary sinus, the required amount of osteoplasty is laid inside. Synthetic and natural materials can play its role. In this case, it is possible to restore the height of the bone tissue to 6-7 mm, sufficient for implantation of the implant.

Is it possible to perform implantation without bone grafting?

Considering that bone augmentation is a rather traumatic method of treatment, which, moreover, postpones the prospect of implantation with a fixed prosthesis, many patients are interested in whether there is a way to bypass this problem. Read more about bone grafting before dental implants.

Fortunately, there is a reliable technique by which implantation is carried out without bone grafting. For example, you can opt for zygomatic implantation, which is very popular among patients with significant bone defects.

This technique is based on implant placement not in the jawbone, but in the cheekbone. The bone tissues in this part of the skull are not prone to atrophy, and once installed and accustomed to the implant is able to stand without any problems for several decades, or even the whole life of a person.

Such efficiency is connected not only with the properties of the bone, but also with the features of the procedure and the implant itself. Consider the advantages of the procedure on the example of Zygoma products (USA):

  1. With zygomatic implantation, an implant is implanted 5 times larger than a classic one. It can be up to 5.25 cm long.
  2. It has a helical cylindrical structure and is coated with a special composition of titanium and phosphorus, which contributes to the fastest and highest quality fusion with bone tissue.