Also known as:
Additional notes on names/types:
The World Health Organisation has grouped different types of osteosarcoma depending on what part of the bone they develop in and the appearance of the cells under the microscope.
Central osteosarcoma (also called medullary or intramedullary osteosarcoma) affects the interior of the bones.
The different types are: conventional (the most common type, with osteoblastic, chondroblastic and fibroblastic forms), low-grade, telangiectatic, and small-cell osteosarcoma. The last two are more aggressive forms of the disease.
Surface osteosarcoma (peripheral osteosarcoma) affects the outer parts of bones.
The different types are: parosteal (in the outermost layers of the bone surface), periosteal (in the membrane that surrounds bones), and high-grade surface osteosarcoma (thought to be a progression of parosteal chondrosarcoma).
How rare is osteosarcoma?
In the UK and Europe the usual definition of a rare cancer is one that occurs in less than 6 people out of every 100,00 each year. Because there are around 200 rare cancers, this means that they make up about 24% (nearly a quarter) of all cancers. According to sarcoma UK, there were 158 cases of osteosarcoma in England in 2019, an incidence of 0.28 cases per 100,000. Worldwide the incidence is reported as being 0.34 cases per 100,000 people. The difference in the numbers reflects the rarity, as a handful of cases can have a big effect on the apparent incidence. There is a slightly higher incidence of osteosarcoma in young people of black or hispanic origin whilst people with a white background are more likely to be affected in older age groups.
Osteosarcoma affects two different age groups. The first is adolescents and young adults, commonly between 10 and 14 years, although it can appear in young adults when osteosarcoma is associated with the adolescent growth spurt. The second group are over 60 and often have other conditions affecting their bones, such as Paget’s disease. There are slightly more males affected than females – about 1.4 males for every female.
What is osteosarcoma?
Osteosarcoma is a type of primary bone cancer – one that starts in the bones rather than spreads there from other sites. This cancer is called a sarcoma, a type of cancer that affects the bones and the soft tissues of the body such as muscle, fat, nerves and ligaments. It might be a surprise to discover that cancer can start in bones, but although much of the structure of bones is made of materials that aren’t alive, bones contain very many different types of cells and any of them can become cancerous.
The picture below shows the structure of a long bone, such as the femur or thigh bone.
Bone is made and maintained by different types of bone cells as in the picture below. They all start as osteogenic stem cells in the bone marrow, then specialise to produce cells with different roles in our bones.
Osteoblasts (“bone germinators” or “bone makers”) make bone by producing a net of tough collagen fibres – collagen is the protein that makes up an important part of many connective tissues in the body such as tendons and ligaments. They then add calcium phosphate that eventually hardens to a mineral called hydroxyapatite. The new bone material is called osteoid. The osteoblasts actually build themselves into the bone and become osteocytes (“bone cells”) which help to maintain the bone. Osteoclasts (“bone breaker”) release an acid and enzymes that dissolve bone destined to be repaired or remodelled before absorbing the materials for re-use or disposal.
Bone remodelling is a continuous process that keeps bone in good condition in response to stresses placed on it. Astronauts who spend long periods in zero gravity lose up to 2% of their bone mass every month as the osteoclasts break down more bone than is replaced. It can take many months for this bone to be replaced. Equally, people who do weight bearing sports have higher bone density than the general population.
In osteosarcoma it is the osteoblasts, or the osteogenic stem cells that become osteoblasts, that begin dividing uncontrollably. In particular for young people, it is the cells at the ends of bones where they are growing that are most likely to be affected. This is thought to be because they are already actively dividing and so are more vulnerable to developing mutations that lead to cancer.
The most common sites for osteosarcoma are the growing ends of the femur (thigh) and tibia (shin) at the end nearest the knee. They also form in the humerus (upper arm), pelvis and lower jaw. Osteosarcoma in the jaw can sometimes be picked up by dentists, especially on routine dental x-rays. When osteosarcoma is a development of Paget’s disease in older patients it is often flat bones such as the pelvis that are affected. Paget’s disease is a condition where the bone absorbing osteoclasts become overactive and the bone making osteoblast over-react, producing too much, badly formed bone.
In the nucleus of our cells is the iconic molecule of inheritance, DNA. It looks like a twisted ladder where the order of the rungs acts as a simple alphabet, spelling out the instructions for everything that our cells make and do. A gene is a short section of DNA that contains the instructions for making one protein – proteins make up much of our bodies and have many other functions (including enzymes)..
We can find the order of these letters by sequencing the DNA. Changes to the sequence are called mutations. Some mutations have little effect on us, but others can lead to cancer by changing the amount or activity of the proteins that are made.
Some cancers have a very characteristic mutation that can be used to both confirm the diagnosis and as a potential target for developing drugs to treat the disease. Scientists have analysed the DNA sequence of many tumours from people with different types of osteosarcoma. They discovered a wide variety of changes, from ones that either damage or amplify certain genes, others that change the way the genes are used as well as huge mutations where large pieces of DNA get moved to different parts of the genome.
Most of the mutated genes that they found were ones that produce proteins called tumour suppressors that repair damage to DNA or stop damaged cells from dividing. The most common are called TP53 and CDKN2a and are often mutated in cancer, allowing even more mutations to occur.
Osteosarcoma tends to spread to the lungs and tumour cells found there have often gained many extra mutations.
There are no risk factors for osteosarcoma that can be controlled by an individual. As the condition is associated with the teenage growth spurt and patients tend to be taller, there is a possible connection with rapid bone growth.
Some very rare inherited conditions increase the risk of developing osteosarcoma. A condition called hereditary retinoblastoma that increases the risk of developing a form of eye cancer in children is caused by a faulty gene called Rb1. This gene is also mutated in about a third of osteosarcomas.
Rb1 is one of a group of proteins called tumour suppressors which are involved in repairing damage to DNA or preventing cells from dividing if they are damaged.
Rb1 mutations are found in about a third of osteosarcomas.
Other conditions that can increase the chance of developing osteosarcoma include Li Fraumeni syndrome, Bloom syndrome, Rothmund-Tompson syndrome, Werner syndrome, Paget’s disease as well as a long list of chemicals, radiation, bone injury and bone infections.
Common symptoms are a combination of pain swelling, redness in the bone as well as weight loss, fever and tiredness. Around half of osteosarcomas occur at the end of the femur near the knee. In young people symptoms such as knee pain may be initially mistaken for growing pains, sporting injuries or non-cancerous conditions such as Osgood Schlatters disease. Often a fast growing lump can be seen or felt. Rarely, the weakened bone can break spontaneously, or after a minor injury.
There is not a specific blood test to diagnose osteosarcoma, but the level of an enzyme called ALP (alkaline phosphatase) will be raised showing that there is a lot of bone making activity from the osteoblasts.
X-ray – typical images
If a doctor suspects that symptoms need further investigation an X-ray is often the quickest way of getting information. An X–ray will be able to detect if there are any changes to the bones. There may be signs of bone destruction – the bone might look mottled or moth-eaten. Tumours near the surface may be growing very quickly so the new bone doesn’t have time to fully harden other than at the edges creating a characteristic triangle (a little like a volcano). There may be fluffy looking growths, unusual new bone or extensions into the soft tissue. Very rarely will a fracture or break be seen (the exception is the telangiectatic form, where breaks are more common).
MRI – magnetic resonance imaging.
This type of scan allows doctors to discover a lot more about a potential osteosarcoma. New bone, soft tissues , fluid build-up and bleeding can be seen and the scan can show exactly where the tumour is and if it has spread into the surrounding tissue. It can also be used to follow the effect of any treatment.
These are both scans that use radiation in a safe way, usually to pick up any metastatic tumours that have formed away form the original site.
This is where a small piece of the tumour is removed and studied under a microscope by a histologist (a scientist who studies cells). They will be able to confirm whether the tumour is an osteosarcoma, and what type it is, if it is another type of cancer, or a benign tumour (non-cancerous type that won’t spread). Biopsies are usually taken with a long needle and the path taken by the needle will be recorded, sometimes using a small tattoo to mark the site. The tissue that the needle went through will need to be removed when any surgery is done because tumour cells disturbed by the needle can be spread through the healthy tissue as the needle is removed.
As the genetic changes in osteosarcoma are so variable there are few genetic tests available to help with diagnosis. The first is for extra copies of a gene for a protein called mdm2. Mdm2 helps switch off an important protein called p53, sometimes called the “guardian of the genome” as it repairs DNA and helps protect cells from becoming cancerous. Only three types of osteosarcoma are known to have extra mdm2, parosteal osteosarcoma, dedifferentiated parosteal osteosarcoma and low grade central (intramedullary) osteosarcoma. As not all cases of these osteosarcomas have this mutation, a negative result does not rule them out as a possibility.
The NHS will also do tests for other genes called NTRK1/2/3. These are genes for part of a chain of messengers that can be mutated to a form that tells cells to divide uncontrollably. Although very few osteosarcomas will have this mutation, drugs that stop NTRK acting (larotrectinib) can help slow the disease if a patient has tested positive for it.
What are the current treatment options for osteosarcoma?
In the past the only available treatment for osteosarcoma was to amputate if the tumour was in a limb or to remove as much as possible if the tumour was in another bone. Only 20% of patients survived. Today surgeons still need to remove the tumour with a wide margin of healthy tissue to avoid leaving any cancer cells, but amputation is reserved only for the most difficult to treat tumours that can’t be removed without damaging nerves or blood vessels that are essential for the limb to function.
The major improvement is in limb-sparing or limb-salvaging surgery that removes the tumour without damaging the limb too much or repairs/replaces the affected bone. An endoprosthesis – an artificial bone that replaces the original one can be used. For young people who are still growing it can include a section that originally could be extended in a small operation. Newer versions use an inbuilt magnet that rotates to turn a screw that lengthens the device when it is put in a rotating electromagnet. This avoids further surgery. Alternatively a patient’s own bone can be used. The fibula – the smaller bone in the lower leg often makes a good replacement as it is the right shape and size.
Osteosarcoma wasn’t treated with chemotherapy until the 1970s when adding drugs such doxorubicin (Adriamycin), methotrexate and bleomycin increased the survival rate to 50%.
Today, chemotherapy is usually given before surgery (neoadjuvant chemotherapy) and after surgery (adjuvant chemotherapy) with small variations depending on the type and grade. For low grade tumours that are reduced before surgery when all of the tumour is removed , further treatment might not be needed.
Most of the drugs used for osteosarcoma are commonly used for many cancers.
Doxorubicin (Adriamycin) damages the DNA in dividing cells as does Ifosfamide and cisplatin. Methotrexate is a drug that affects the production of the “rungs” of the DNA ladder, but it must be given at a very high dose, so can have very unpleasant, even lethal side effects. It is often given with another drug called leucovorin to help replace the essential folic acid that methotrexate removes.
More recently a drug has been approved in Europe called mifamurtide (Mepact).
Disease causing bacteria have molecules on their surface that activate white blood cells, which then attack and destroy any invading pathogens. Mifamurtide was created by making a molecule that looks like one from mycobacteria that cause diseases such as tuberculosis and leprosy. The molecule tricks the immune system into activating a response to bacteria that aren’t there, but the activated white cells will also attack some types of cancer cells including osteosarcoma without harming normal cells.
Radiotherapy is not often used for osteosarcoma as it can interfere with the wound healing after surgery and the tumours don’t often respond to it. Under certain circumstances it might be used if a patient’s medical team thinks it is suitable.
What current clinical trials are there?
Information current as of: 19th June 2023.
Historically there have been very few clinical trials for osteosarcoma as there were very few patients and the disease is genetically complicated so it has not been suitable for trials of many of the new targeted drugs.
Current trials are looking at improving the endoprostheses used in limb salvage surgery and a fluorescent dye called indocyanine green that makes tumours more visible during surgery,
IMMUNOSARC. In order to stop our bodies producing an immune response against ourselves there are ways of switching off some of the white blood cells. On the surface of some white blood cells (T-cells) is a protein called PD-1. If another protein called PDL-1 sticks to it, the T-cells don’t attack.
This trial is looking at the combination of sunitinib, a drug that blocks the transfer of “grow” messages in the cancer cells and nivolumab. Nivolumab (Opdivo) is an antibody that sticks to the PD1, stopping the PPDL1 from sticking, which means the T-cells don’t shut down. This type of drug is called an immune checkpoint inhibitor.
SCOOP: The final trial is looking at a drug called niraparib (Zejula) that blocks another method of DNA repair leading to a build up of small breaks in the DNA that can eventually kill dividing cells. It is combined with Dostarlimab (Jemperli), which is another checkpoint inhibitor similar to Nivolumab.
Where can I find support groups?
Awareness, events and symbols
All sarcomas have July as their awareness month.
The ribbon for sarcomas is yellow.