Introduction

Tumoral calcinosis is a rare type of calcinosis cutis and is a condition of unknown origin, comprised of abnormal calcium deposits in soft tissues, primarily around joints. These calcified masses can lead to pain, restricted movement, and complications depending on their size and location. As it builds up into a large calcium mass, it can appear like a tumour, thus resulting in the name ‘tumoral calcinosis’. Despite extra calcium deposits in the body, circulating calcium levels remain normal, whereas phosphate levels increase since the kidneys don’t remove enough of it in the urine. Although surgical removal and other interventions are commonly considered for this condition, medical management, including the use of bisphosphonates, has emerged as a promising approach because there is often recurrence with surgical removal.

Bisphosphonates are a class of drugs primarily used to treat bone-related conditions such as osteoporosis and Paget’s disease. These medications inhibit the activity of bone cells called osteoclasts, thus affecting how bone is remodelled over time. This has led researchers to explore their potential benefits in conditions involving pathological calcium deposition, such as in tumoral calcinosis.

What causes Tumoral Calcinosis?

There are a number of different gene mutations that have been linked to tumoral calcinosis.² These include:

• FGF 23 (Fibroblast Growth Factor 23) mutations
• GALNT3 (Polypeptide N-Acetylgalactosaminyltransferase 3) mutations
• KL (Klotho) mutations
• SAMD9 (Sterile Alpha Motif Domain Containing 9) mutations 

FGF23 is a protein produced by bones using the FGF23 gene, and it interacts with the kidneys to regulate the amount of phosphate (a charged phosphorus and oxygen compound) in the body. Phosphates are important for bone remodelling. When the FGF23 gene is mutated, phosphate isn’t removed from the body enough in most cases, leading to excessive amounts of phosphate in the blood. GALNT3 helps ensure the FGF23 is formed properly, so mutations in this gene can also lead to high amounts of circulating phosphate and tumoral calcinosis (hyperphosphatemic familial tumoral calcinosis). KL is responsible for aiding FGF23 to interact with the kidneys, so when this is mutated, FGF23 cannot properly perform its function, even if the protein itself is fine.

High levels of circulating phosphate can bind with circulating calcium, condensing to form solid masses which can then invade local tissue.

In some rare cases of tumoral calcinosis where circulating phosphate levels are normal, SAMD9 mutations may be responsible for tumoral calcinosis as it partially controls cell duplication and movement.

As tumoral calcinosis is a rare condition and only one type of the different calcinosis cutis family of illnesses, it is very difficult to gauge the exact incidence rate of this disease.

Where in the body can masses be found?

Tumoral calcinosis can lead to calcium deposits anywhere in the body, but most commonly, the joints are affected in this type of calcinosis cutis.² Commonly affected joints include:

• Hips
• Elbows
• Shoulders
• Ankles
• Wrists
• Spinal cord
• Jaw

The joints may not be painful, and only solid lumps may be felt, but a nerve may be pressed, thus leading to tenderness.

Treatment options

X-rays, CT scans, and MRIs can all be used to diagnose tumoral calcinosis alongside blood tests. Many other conditions can present in a very similar way, ranging from calcium deposition in different parts of the body, e.g. in the skin, to muscle turning into calcified tissue. As such, great care should be taken upon diagnosis to prevent misdiagnosis. Typically, an orthopaedist will be responsible for this due to the rarity of the condition.

Upon diagnosis, different treatment options are available.

A low-phosphorus diet can also be helpful, which means avoiding foods high in phosphorus such as the following.

• Cheese
• Milk
• Yogurt
• Organ meats like livers and kidneys
• Processed meats like hot dogs
• Nuts
• Seeds
• Soy products
• Lentils
• Chickpeas
• Beer
• Chocolate drinks
• Frozen meals
• Cakes
• Cookies
• Doughnuts

When dietary changes are insufficient, surgical removal may be necessary. However, surgical excision can often result in redeposition of the calcium, thus leading to more masses and the need for frequent surgery. This is because the causes of tumoral calcinosis are genetic, and so removing the masses alone doesn’t change why they were deposited in the first place. 

As such, the use of bisphosphonates has been explored. They can be used on their own to manage calcium and phosphate levels or in conjunction with other treatments such as lifestyle changes and surgery. 

Types of bisphosphonates used in tumoral calcinosis

Intravenous bisphosphonates

Intravenous bisphosphonates are bisphosphonates that are injected directly into the bloodstream. Two types have been trialled for this use, pamidronate and zoledronic acid. Zoledronic acid has a longer-lasting effect than pamidronate, though both are used in cases of advanced calcification due to the method of drug delivery.⁶

Pamidronate can help in numerous ways, including inhibiting the activity of bone remodelling cells called osteoclasts, which reduces the amount of calcium released into the bloodstream from bones. It can also balance phosphate and calcium levels in the bloodstream, thus dealing with the hyperphosphatemia (high circulating phosphate levels). Maintaining these circulating levels can help prevent the recurrence of masses after surgery.⁵ Its anti-inflammatory effects reduced inflammation around the tumoral mass, thus relieving pain, and some studies have shown that it can also reduce the size of the mass when given intravenously for a few hours, every couple of months.^3,4,5 

Zoledronic acid has very similar effects, and due to its longer-lasting effects, infusions may be given over a shorter period of time.^7,8 Indeed, 15-30 minute transfusions every 3-6 months have been given with monitoring to avoid circulating calcium levels from falling too low (hypocalcaemia).⁸ 

Oral bisphosphonates

Bisphosphonates can also be prescribed to be taken orally. These include alendronate and risedronate, both of which have similar modes of function within the body.

Alendronate reduces the activity of bone osteoclast cells, slowing down the natural breakdown of bone and thus decreasing calcium release into the bloodstream.⁹ With less circulating calcium, lower calcium-phosphate complexes form, and thus there are fewer calcium masses. In some cases, this can potentially shrink existing masses as well.⁹

Additionally, this bisphosphonate has anti-inflammatory effects so it can reduce inflammation of the calcified masses. This reduces tenderness around the lumps and improves quality of life.⁹

This can be used on its own to try to alleviate tumoral calcinosis, or it can be used in conjunction with surgical excision to prevent more calcified masses from depositing.⁹

Risendronate also does all these things, but it also promotes phosphate storage in bones, which reduces the levels of phosphate available to bind to free calcium in the blood.¹⁰ Though it has been proved effective with other types of calcinosis, specific treatment for tumoral calcinosis with risendronate has not yet been conducted.¹⁰

Depending on your personal health needs, your healthcare provider may choose one of these. There is some research to show their effectiveness, but more extensive research would be useful in these cases. 

Side effects of bisphosphonate use

Although there are many advantages to using bisphosphonates for tumoral calcinosis treatment, some pitfalls exist due to the systemic effects of these drugs.^2,6 These can include nausea, heartburn, and other gastrointestinal issues with oral bisphosphonates. Additionally, hypocalcaemia may result, and due to the effects on bone remodelling, bone pain may occur. With intravenous bisphosphonates, symptoms like fevers, muscle pain, and fatigue are also possible. 

Rarely, more aggressive side effects may occur like oesophageal ulcers, femur fractures, bone death in the jaw (osteonecrosis of the jaw), kidney damage in those with existing renal issues, and severe hypocalcaemia. 

This is why it is very important to follow your healthcare provider’s instructions when prescribed bisphosphonates, especially as taking these improperly can increase the likelihood of side-effects. 

Summary

Tumoral calcinosis is a genetic disease that leads to calcium irregularly depositing in and near joints, thus forming solid masses that can restrict movement and cause pain, especially when inflamed. Due to the rarity of this disease, an incidence rate has not yet been established. Following dietary changes, surgical excision of the mass is often the next move, but the masses often recur due to the genetic underlying cause of the condition. As such, bisphosphonates have been explored as a means of managing circulating calcium levels to prevent deposition and mass build-up, with some success. However, larger-scale studies are needed in order to increase confidence in using bisphosphonates as a means of treatment for tumoral calcinosis.