Bisphosphonates

Generic Name Brand Name Route Dose
Alendronate Fosamax Oral Pills 10 mg daily or 70 mg weekly
Risedronate Actonel Oral Pills 5 mg daily, 35 mg weekly, or 150 mg monthly
Zoledronic Acid Reclast IV infusion 5 mg yearly

How Do Bisphosphonates Strengthen Bone?

Bisphosphonates have been studied for decades and have proven to be effective in treating osteoporosis. Their mechanism of action is fairly complicated, but if we break it down into a few key steps it becomes much easier to understand.

  • Bisphosphonates are absorbed into your bloodstream and travel to your bones, where they attach to places where osteoclasts recently recycled away old bone.
  • Bisphosphonates enter into osteoclast cells, and once inside, they block important enzymes necessary for osteoclasts to break down bone.
  • The activity of both bone recycling osteoclast cells and bone building osteoblast cells are slowed by bisphosphonates. However, osteoclast cells are more significantly impacted, which allows for an increase in bone density and decrease in your risk of fractures over time.

What Research Says About Bisphosphonates For Osteoporosis

Since the 1990s, the bisphosphonates have been extensively studied to determine how much impact they have on improving bone strength and decreasing your risk of fractures.

Want a quick summary of the results?  Each of these studies lasted 3 years, and aimed to determine how much these medications improved bone health in people with osteoporosis. Let’s take a look at the most important results.

Need all of the details?  I’ve provided a link to the landmark studies used by the FDA to approve these medications. Fair warning… there is a lot of medical lingo and it is easy to get bogged down in the details.

What Happens If You Stop Taking Bisphosphonates?

Have you ever heard of a “drug holiday?” It is probably the most welcomed concept in all of medicine— a period of time that you can COMPLETELY stop taking a medication while still protecting your bones.

In the osteoporosis world, this only applies to the bisphosphonates. Studies have shown that if you take a bisphosphonate for 3-5 years, you may be able to stop taking the medication and continue to have a decreased risk of breaking bones for an additional 3-5 years with few exceptions.

Want a quick summary of the results?  Here are the most important findings.

  • Taking Fosamax and Actonel for 5 years provided 10 years of bone protection.
  • Taking Reclast for 3 years provided 6 years of bone protection.

Still craving all of the details?  Here are the links to the studies which demonstrate the long-term effects of bisphosphonates during drug holidays.

What Are Possible Side Effects?

As with all osteoporosis treatment options, you must carefully balance the risk of side effects associated with the medication, as well as your fracture risk if you choose to avoid treatment. If taken appropriately, your risk for developing side effects while taking bisphosphonates is low. Discuss the need for continued use of bisphosphonates longer than 5-10 years with your medical provider, as this may increase your risk for side effects.

Musculoskeletal Pain Muscle and joint pain is the most commonly reported side effect.
Atypical Femur Fractures An atypical femur fracture is one that occurs in an abnormal location compared to normal. Instead of being by the ball-and-socket joint of the hip, these are located further down the shaft of the bone. While this side effect gets considerable attention, it is extremely rare—studies including over 10,000 patients taking Fosamax for up to 10+ years did not report a single case. The general consensus is that an elevated risk of atypical fractures is primarily seen in those who take bisphosphonates for longer than 5-10 years continuously.
Osteonecrosis of the Jaw ONJ is defined as exposed jaw bone that does not heal within 8 weeks, and often requires surgery to treat. The reported incidence of ONJ is less than 1 case per 100,000 patient years of treatment. It is most commonly seen in those who are currently on chemotherapy, or have previously received radiation to the neck or jaw region. .
GI Irritation This refers to conditions including acid reflux, inflammation of the esophagus and even ulceration of the esophagus and stomach. If taken properly, most studies show the risk of developing GI irritation is no greater than if you took a placebo pill. However, if you have a medical condition that causes difficulty with swallowing, or have a history of a stomach ulcer, it is best to avoid the pill form of bisphosphonates.
Flu-Like Symptoms Reclast infusions have been associated with flu-like symptoms. These symptoms are most likely to occur following your first infusion (32%) and become less likely over time (only 2.8 reported it during the third infusion). Taking Tylenol around the time of the infusions has been shown to decrease the odds of developing these symptoms by 50% or greater.
Hypocalcemia A temporary drop in blood calcium levels has been reported in certain patients taking bisphosphonates. This generally occurs in patients with low vitamin D levels, or other medical conditions which predispose them to the condition. Rarely does this lead to any symptoms.
Kidney Disease Kidney disease, including kidney failure, has been reported in certain patients taking bisphosphonates—particularly those with stage 4 or 5 kidney disease, multiple myeloma, or on long term diuretics.
Heart Arrhythmia A temporarily abnormal heartbeat has been reported in patients taking bisphosphonates. In the HORIZON trial, 6.9% of patients taking Reclast experienced a heart arrhythmia compared to 5.3% of the placebo patients. In this trial, there were no reported adverse events from these temporary arrhythmias.

Prolia

Generic Name Brand Name Route Dose
Denosumab Prolia Injection into the subcutaneous skin tissue performed by a medical professional 60 mg every 6 months

How Does Prolia Strengthen Bone?

To understand how Prolia is used to manage osteoporosis, you must know some basic bone physiology. It may seem complicated, but if we break it down into a few simple steps it becomes much easier to grasp.

  • Bone building osteoblast cells communicate with bone recycling osteoclast cells through chemical messages to control the rate that old bone is broken down and new bone is formed
  • The “ON” signal for bone breakdown is RANKL, and the “OFF” signal is OPG
  • Prolia blocks RANKL—which then decreases the bone breakdown activity of osteoclast cells and allows bone building osteoblasts to “catch-up” in laying new bone

What Research Says About Prolia For Osteoporosis

Prolia has been extensively studied dating back to the 1990s for its effect on your bone density and your risk of breaking bones.

Want a quick summary of the results?  Each of these studies lasted 2-3 years, and aimed to determine how much Prolia improved bone health in people with osteoporosis. Let’s take a look at the most important results.

Need all of the details?  I’ve provided a link to the landmark studies used by the FDA to approve Prolia. Fair warning… there is a lot of medical lingo and it is easy to get bogged down in the details.

What Happens If You Stop Taking Prolia?

Prolia has been shown to increase your bone density and decrease your risk of breaking bones, however, these effects are short-lived after you stop taking the medication.

Want a quick summary of the results?  Here are the most important findings.

  • Spine bone density decreased 6.6% within 2 years of stopping Prolia. 
  • Hip bone density decreased 5.3% within 2 years of stopping Prolia.
  • Your risk of breaking bones returned to your baseline level within 2 years of stopping Prolia.

Still craving all of the details?  Here is a link to the FREEDOM Extension Trial, which demonstrates what happens to your bones when you stop taking Prolia.

If your medical provider recommends that you stop taking Prolia, you will need to transition to another osteoporosis medication to maintain the bone protective effects of Prolia.

What Are Possible Side Effects?

Studies spanning 10 years have shown Prolia to be a safe and effective medication, however, patients have reported side effects while taking Prolia. Your medical provider must balance the benefits of Prolia with the possible risks associated with use of this medication.

Musculoskeletal Pain Muscle and joint pain is the most commonly reported side effect of Prolia.
Atypical Femur Fractures An atypical femur fracture is one that occurs in an abnormal location compared to normal. Instead of being by the ball-and-socket joint of the hip, these are located further down the shaft of the bone. In the FREEDOM extension trial, 1 patient out of 4550 experienced an atypical femur fracture over the 6 year duration of the trial. A separate study monitoring the effects of Prolia over an 8 year period reported no cases of atypical femur fractures. While rare, you should watch for abnormal thigh pain and report this symptom immediately to your medical provider.
Osteonecrosis of the Jaw Osteonecrosis of the jaw is defined as exposed jaw bone that does not heal within 8 weeks. This has been reported as a possible side effect in patients taking Prolia for extended periods of time, and typically involves patients on chemotherapy or who have dental surgery while taking Prolia. In the FREEDOM extension trial, 6 patients out of 4550 developed osteonecrosis of the jaw over a 6 year period. A separate study monitoring the effects of Prolia over an 8 year period reported no cases of this condition. It is important to maintain good oral hygiene and have routine dental examinations while taking Prolia to minimize the risk of this side effect.
Hypoocalcemia A temporary drop in blood calcium levels has been reported in certain patients taking Prolia. This generally occurred in patients with low vitamin D levels, or other medical conditions which predisposed them to the condition. Rarely does this lead to any symptoms.
Immune System Your immune system is your defense against infections. The RANKL that Prolia blocks has also been shown to have a role in certain aspects your immune system. Some studies have shown that Prolia may increase the risk of certain infections, but this has not been consistent among all studies and this remains a theoretical risk at this time.

Forteo

Generic Name Brand Name Route Dose
Teriparatide Forteo Self-administered injection into the subcutaneous skin tissue 20 mcg daily

How Does Forteo Strengthen Bone?

Forteo works differently than other osteoporosis medications—instead of blocking the action of bone recycling osteoclast cells, it directly stimulates bone building osteoblasts to make new, healthy bone. Forteo is a synthetic form of parathyroid hormone. While constantly high levels of parathyroid hormone (a condition called hyperparathyroidism) can weaken your bones, Forteo leads to only a temporary increase in the hormone, which has been shown to strengthen bones over a 2 year period.

  • A temporary increase in parathyroid hormone significantly increases the bone building effects of osteoblasts, and only slightly increases the bone recycling effects of osteoclasts
  • Over the first 2 years of treatment, the rate of bone formation far exceeds osteoclast activity and new, healthy bone is added to your skeleton
  • After 2 years of treatment, the rate of new bone formation plateaus and continued use of Forteo leads to no further improvement in bone strength
  • Since the bone building effects of Forteo run out after 2 years, your medical provider will need to switch you to another osteoporosis medication at that time

What Research Says About Forteo For Osteoporosis

Forteo has been extensively studied dating back to at least the 1990s for its impact on your bone health.

Want a quick summary of the results?  The Fracture Prevention Trial lasted 18 months, and aimed to determine how much Forteo improved bone health in people with osteoporosis. Let’s take a look at the most important results.

Need all of the details?  I’ve provided a link to the landmark study used by the FDA to approve Forteo. Fair warning… there is a lot of medical lingo and it is easy to get bogged down in the details.

What Happens If You Stop Taking Forteo?

Forteo has been shown to improve your bone density and decrease your risk of breaking bones with 2 years of treatment, however, these effects are short-lived if you do not switch to an alternative osteoporosis medication when you stop taking Forteo.

Want a quick summary of the results?  Here are the most important findings. The study compared the effects of 12 months of Forteo followed by 12 months of Fosamax, vs. only 12 months of Forteo and then no additional treatment for 12 months.

  • 12 months of Forteo followed by 12 months of Fosamax led to an increase in spine bone density of 12.1%
  • 12 months of Forteo followed by 12 months of no treatment led to a only a 4.1% increase in spine bone density (8% less than the other group!)

Still craving all of the details?  Here is a link to the Parathyroid Hormone and Alendronate for Osteoporosis Trial, which demonstrates what happens to your bones when you stop taking Forteo.

Your risk of breaking bones appears to return to pre-treatment levels within 2 years of stopping Forteo. To maintain the bone protective effects of Forteo, you will need to switch to another osteoporosis medication after completing the FDA recommended 2 years of Forteo.

What Are Possible Side Effects?

Your medical provider must balance the benefits of the Forteo with the risks associated with use of this medication. Studies spanning the FDA approved two years of treatment have proven Forteo to be a safe and effective medication, however, below is a list of potential side effects which must be carefully considered.

Headache/Dizziness Headache and dizziness were the most commonly reported side effects of Forteo. Studies vary in how often these symptoms are reported—from no difference compared to placebo, up to 3% more frequently than placebo.
Muscle Cramping Muscle cramping is another one of the more commonly reported side effects of Forteo. In the Fracture Prevention Trial, 3% of patients receiving Forteo reported muscle cramps, compared to only 1% of placebo patients.
Hypercalcemia A temporary increase in blood calcium levels occurred more frequently in patients taking Forteo. This rarely led to any symptoms, but there are a few reported cases of severe hypercalcemia leading to hospitalization.
Gout Elevated uric acid levels are responsible for flares of gout. Forteo may increase blood uric acid levels, which can increase the risk of gout in select patients. Large studies including the Fracture Prevention Trial did not find any significant difference in gout flares between patients taking Forteo and those taking the placebo, but other studies have indicated an increased incidence of gout.
Osteosarcoma? Osteosarcoma is a rare form of bone cancer which can lead to pain, disability, and even death. Early Forteo studies were cancelled after osteosarcoma was incidentally discovered in a study involving rats. At that point, more research needed to be conducted to prove the safety of Forteo in humans before any further trials could resume. When we look deeper into the rat study, the rats in the trial that developed osteosarcoma were exposed to highly toxic doses of Forteo for a duration of time similar to the entire lifespan of the rat. These are doses and a duration of treatment that humans would never be exposed to. A separate study exposed monkeys to Forteo doses 10-times greater than that recommended for human use, and no instances of osteosarcoma were reported. A thorough review of all studies dating back nearly 20 years has never shown Forteo to increase the risk of osteosarcoma in the human population. To summarize, does Forteo cause osteosarcoma in humans? There is no evidence in human studies taking FDA-approved doses that it does. With that said, if you have a history of osteosarcoma or Paget’s disease, it is best to avoid Forteo.
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