Osteoporosis Medications

A Look At the Commonly Prescribed Medications used to Treat Osteoporosis and Osteopenia

The use of osteoporosis medications is not a topic to take lightly.

Although these drugs have passed rigorous trials before being allowed on to the market, and have been demonstrated to either reverse or slow down losses in bone density and changes in bone micro-architecture, there are many other issues that need to be considered before starting a course of osteoporosis drugs.

There are many side-effects associated with the use of these drugs — jaw necrosis for example — and there is also a large cost element to consider. Although generic drugs may cost from as little as a $100 a year, the use of newer patented drugs and injections for osteoporosis may run into thousands of dollars a year. If you live in a country that has national health insurance, or have an insurance policy that covers the cost of your prescribed medicine, then this may not be an issue. However, if you need to pay for you own medicine then its cost may be a major issue when considering the best osteoporosis treatment options for you.

The non-medication route

Osteoporosis treatment guidelines mean that most doctors will neither suggest nor prescribe medication to people who have osteopenia and have not had a fracture. They will suggest that bone density can be maintained or even improved through the use of lifestyle changes. Perhaps the major changes that will be addressed are ones diet and exercise routine. It is often the case that your practitioner will suggest that you eat a diet (or more likely take supplements) that is rich in the minerals calcium, magnesium, zinc, and phosphorous; and in vitamins D and K — all of these nutrients are known to play an active role in the bone remodeling cycle.

Further to this it will usually be suggested that you partake in a weight-bearing exercise program —this could include exercises such as walking, stair climbing, jumping (if you are not thought to be at risk from fracture) and dancing and weight training. Although walking is very important in the fight against losing bone density, it is only effective to a certain extent; walking for an hour is not thought to be more effective than walking for 10 minutes a day. However, a walk done in combination with a light jog — a walk jog — has been shown to increase spine and hip bone mineral density levels when performed over a longer time period — around 20 minutes, three of four times a week. As one of the biggest problems associated with thinning bones is the increased risk of bone fractures, your practitioner is likely to suggest exercises that aid in balance, two of the exercises that are likely to be suggested are T’ai chi and water based aerobics.

It is also important to limit other risk factors that are known to be associated with osteoporososis; these include the consumption of soda, smoking, excess alcohol, being under-weight, and endurance training.

Osteoporosis Drugs

Although your doctor will most likely suggest that you do not take osteoprososis drugs if they can be avoided, it may be necessary if they consider that your bone mineral density levels put you at high risk of breaking bones. These will usually be prescribed alongside a recommendation of calcium and vitamin D (and other nutrient) supplementation, and advice to carry out weight bearing exercises, and avoiding risk factors such as outlined in the previous section.

There are many different medications available on the market. Perhaps the best-known treatments are the bisphosphonates, some of which are available as generic drugs. There are many other osteoporosis medications that have been developed in recent years; many of these are given by a six-monthly or yearly injection. There is a large range in the cost associated with these medications, and this may be needed to be taken into account when choosing which treatment that you receive.

Bisphosphonates Osteoporosis Medications

These are the commonest form of osteoporosis medication and may also be referred to as diphosphonates. Trials have shown that they are able to reduce the likelihood of fractures in people who have already had a previous bone breakage. In addition to being used in the treatment of osteoporosis, this medication (in the form of Zoledronic acid) is also associated with reduced risk of the recurrence of breast cancer.

Bisphosphonates work by mimicking the structure of pyrophosphate. By doing so, they are to inhibit enzymes that are involved in the bone breakdown process (carried out by osteoclasts). Bisphosphonate binds to calcium, the calcium then accumulates in the bone tissue, where it then inhibits skeletal break down by the osteoclasts.

There are two major classifications of bisphosphonates used for osteoporosis therapy, the Nitrogenous; and the Non-Nitrogenous classes. These work to prevent bone loss by different mechanisms.

The nitrogenous bisphosphonates act by binding to an enzyme known as FFPS, and in doing so disrupting the HMG-CoA reductase pathway. This leads to a process called prenylation. Prenylation of proteins then affects the osteoclasts ability to play its role in the bone remodeling cycle. Some of the best known drugs that make use of nitrogenous bisphosphonates are Aclasta; Actonel; Aredia; Boniva; Fosamax; Nerixia; and Zometa.

The second class, the non-nitrogenous group, functions by forming nonfunctioning molecules that compete with ATP (the energy molecule). This affects the energy metabolism of osteoclasts, leading to apoptosis of the osteoclast cells. The overall effect is that there is slow down in the rate of bone breakdown. There are three major medications that make use of this group of bisphosphonates: Bonefos; Didronel; Loron; and Skelid.

There is a large range in the affinity of bisphosphonates with the bone surface. This leads to two scernarios: drugs that have high affinity (zoledronic acid: Aclasta/Reclast/Zometa) easily bind, and remain in the bone tissue, but they spread very slowly through the bones. Lesser affinity drugs (clodronate: Bonefos/Loron) spread quicker through the bone, but do not remain there for as long.

Effectiveness of Bisphosphonates

There has been much research into the impact of the use of this classification of osteoporosis drug. Following a three-year treatment, studies have shown that the use of bisphosphonates can increase bone mineral density in the hip by three to six percent; and in the spine by five to eight percent. The incidence of non-vertebral fractures in people treated with alendronate (Fosamax); risedronate (Actonel); and zoledronic acid decreased by 25 to 40%, and from 40 to 60% in the hips.

Fosamax Pills: Photograph by Neofedex.

Many controlled trials have shown positive impacts of treatment over a long period. For example, the use of zoledronic acid and Risedronate has been demonstrated to reduce fracture occurrence within six to twelve months of use; and for this effect to be sustained for a five to eight year period. As there is an accumulation of the bisphosphonates in the bone, there is a creation of a reservoir of the drug. This means that once treatment has finished the medication remains effective. Both alendronate and risedronate remained effective for one to two years after treatment with them had ended (following three to five years of use). Because of this, many researchers have recommended a drug use holiday after a period of five to ten years of use. The length of treatment required, and the drug holiday period allowed would be based on individual patient requirements: For example, lower risk patients, who have seen a stabilization of bone mineral density levels, and have not had a fracture, may consider a holiday after 5 years of bisphosphonate use. On the other hand, higher risk cases may require at least ten years use, and the use of a non-bisphosphonate drug during the holiday period.

Bisphosphonate Side Effects

As with many drugs, many side effects can occur when taking bisphosphonates as an osteoporosis medication. Some of these are minor, and can largely be avoided, whilst others are of major concern and should be discussed with your medical practitioner before you consider taking this form of treatment.

Two of the main minor side effects of this class of osteoporosis drug are upset/pain in the stomach and nausea. This is largely a result of the medication causing irritation of the esophagus. This can largely be overcome by taking the oral bisphosphonate treatment on an empty stomach, along with a glass of water. Furthermore, you should remain in an upright position for at least 30 minutes, preferably an hour. This will prevent the medicine from washing back up to the esophagus. Incorrect use of the medication may lead to ulcers in the esophagus. If you find that you are having trouble taking bisphosphonates orally you may like to consider injected forms of bisphosphonate therapy, these include zoledronic acid and Ibandronate (Boniva).

If you have any signs of the more serious side effects, such as a painful jaw, swelling in the joints; increased pain in the joints, muscles or bones; black stools; vomiting; increased heartburn; difficulty in swallowing or breathing; or allergic reactions such as rashes, itching and dizziness then contact your doctor immediately. This is not an extensive list of known side effects; it is recommended that you read the pamphlet that comes with your medication in full for a more extensive list.

In addition to the above effects, there are some serious complications that may develop through the use of bisphosphonates; these include jaw necrosis, cardiac arrhythmia, and atypical fractures. There is a prevalence of jaw necrosis in people with cancer, who have had major dental work, or have inflammatory dental diseases. If you have any of these conditions, then the use of bisphosphonates is not recommended, your doctor should know this, and though it may mean that you will require a more expensive treatment, the reasoning behind the decision will be just.

The development of atypical fractures has been reported in people taking alendronate long term; this is thought to be a result of long-term suppression of bone turnover affecting the bone remodeling process and that of accumulated bone micro-damage. This can lead to increased skeletal fragility and stress fractures; there is also an increase in pain in these fractures. People on long-term bisphosphonate therapy will require consultation from an orthopedic surgeon if there are signs of pain in the groin or upper thigh regions.

Strontium Ranelate – Protos/Protelos

This mineral has a similar molecular make up to calcium, and around 99% of the body’s strontium is found in the bones or teeth. Research has revealed that when taken in the form of strontium ranelate that the mineral is able to promote bone growth, and increase the density of bones. This results in a lowering of vertebral, peripheral and hip fractures in postmenopausal women in clinical trials. The drug is marketed as Protos or Protelos and manufactured by Servier Laboratories. It is currently approved for use in over 70 different countries and registered in over 100: these include the entire EU, Australia, and many Asian countries. In the EU it is approved for the treatment of osteoporosis in men and postmenopausal women.

The drug works by increasing activity of osteoblasts (the builders in the bone remodeling cycle). There is also an associated increase in collagen synthesis, and a modulation of the OPG/RANKL system. There is also an associated decrease in osteoclast resorbing acticity and apotosis.

The analysis of the drug revealed over a three-year period revealed that it could reduce the risk of vertebral fractures by 41% in women who had osteoporosis, and reduce hip fracture incidence by 36% in high risk groups. A further study demonstrated that it could reduce first vertebral fracture risks by as much as 72%. It is especially of use in older patients, and in men, where use of the drug increased bone density by 7% one year after the initiation of treatment.

Strontium ranelate is taken on an empty stomach, at least two hours after the last meal, at bedtime. The drug is taken daily comes in powder form (2g sachet) and diluted in 30ml of cold water. The solution should be stirred (it will have  a milky appearance) and drank straight away.

Box of Protelos sachets. Image by Pifrac.

Strontium Ranelate Side Effects

The most common side effects of strontium ranelate are diarrhea, headaches, rashes, and nausea. These effects do not happen at high rates, and usually last for less than three months. A more serious impact is an increased risk in the formation of blood clots; therefore, the drug is not recommended for those with a history of this condition (thromboembolism). Clinical trials also suggested that there could be rare incidences of memory loss, and fitting. Other people who should not take this medication are those with kidney conditions; or suffer from phenylketonuria. As strontium ranelate is a relatively new drug on the market, there is little known of the effects of its long-term use.

Denosumab – Prolia, Xgeva

The human monoclonal antibody Denosumab acts by inhibiting RANK signaling and is marketed as Prolia for postmenopausal osteoporosis treatment in women. It is also marketed as Xgeva as a medicine for people with bone metastases. It is manufactured by Amgen and distributed internationally by GlaxoSmithKline.

Denosumab works by inhibiting RANK ligands that are present on the surface of the precursors of osteoclasts. This mimics natural osteoprotegerin; this cytokinine receptor acts as a decoy for RANK ligands, but it is present at reduced concentrations in people who have osteoporosis.

In trials, it is reported that the use of Prolia for osteoporosis could reduce the risk of fractures in postmenopausal women who had had two, or greater, vertebral fractures by 35%. Furthermore, there was an over 2-fold reduction of the incidence of bone fractures in men who were receiving hormone-deprivation therapy for the treatment of prostate cancer. Further studies, carried out in women who had osteopenia (bone mineral denstity T-scores of between –1 and –2.5) revealed that the use of denosumab resulted in a T-score increase of 6.5%, this can be compared to a lowering of T-score by 0.6% in the control group. Other studies have demonstated thet the use of denosumab is more effective in increasing the total bone mineral density of the hip in comparison to the bisphosphonate Alendronate.

The drug is given to women who have postmenopausal osteoporosis and have already had some kind of fracture, or considered to be in a high-risk group of receiving one. Denosumab is given in the form of a subcutaneous injection twice a year (every six months); this may be given in the upper arm, thigh or the abdomen. As this osteoporosis drug can lead to lower blood calcium levels it is usually taken alongside calcium and vitamin D supplements, and not given to people who have low blood calcium levels. Although XGEVA and Prolia are marketed as different drugs they both contain denosumab as the active compound and should not be taken together. Other conditions that should be discussed with your doctor before taking this drug as a treatment for osteoporosis include having had surgery to the thyroid/parathyroid glands; kidney problems; and planned dental work; this medication has a link with jaw necrosis so it is usually necessary to have a thorough mouth examination before starting treatment. The treatment is usually only given to postmenopausal women and should not be taken by pregnant or breast feeding women.


Prolia Denosumab Side Effects

Some of the known side effects of Prolia/denosumab use include pain in the back, arms and legs; increased cholesterol levels; cataracts; urinary infections; skin infections; constipation; and sore muscles. Use of the medicine may also lead to a slowdown in the rate of the healing of fractures. It has been reported that osteonecrosis and abnormal thighbone fractures may occur.

Go to part two of the osteoporosis medications guide.