New Osteoporosis Drug Abaloparatide: Not A Major Leap Forward for Our Bones
Abaloparatide is being heralded as a big improvement over teriparatide. It isn’t. This drug is not a major leap forward for our bones.
Abaloparatide, which doesn’t yet have a catchy trademark name, is just a slight tweak on teriparatide, has all the same adverse effects, and just like teriparatide, abaloparatide’s anabolic effects on bone start to drop off after 12 months, possibly sooner.
Before we get into the post, you can find information on teriparatide and it’s most common brand names here on Mayo Clinic.
What Teriparatide and Abaloparatide Are, What They Do, and How They Differ
Teriparatide is a made-in-the-lab copy of a small fragment of parathyroid hormone (amino acids 1-34 of parathyroid hormone). Real, human parathyroid hormone (PTH) contains 84 amino acids.
Abaloparatide is another made-in-the-lab copy of a section of a protein related to parathyroid hormone called human parathyroid hormone-related protein (amino acids 1-34 of PTHrP). (The first 34 amino acids in both PTH and PTHrP appear to be the most “active” section in both PTH and PTHrP.)¹
PTH and PTHrP regulate calcium metabolism in our bones and kidneys. Both PTH and PTHrP exert their calcium-regulating effects by binding to a receptor called PTH1R. This receptor, PTH1R, is found in high levels in both our bones and kidneys, and when activated (by PTH or PTHrP), transmits signals that keep calcium levels in the bloodstream at a constant level, primarily by activating both osteoblasts, the specialized cells that build new bone, AND osteoclasts, the specialized cells that break down worn out or damaged bone. PTH and PTHrP also increase calcium’s reabsorption in the kidneys.
In addition, PTHrP further increases calcium availability by increasing the production of vitamin D receptors, thus increasing our cells’ sensitivity to the hormonally active form of vitamin D, 1,25-D(OH)2D3, which is the form in which vitamin D increases intestinal calcium absorption. Our bodies are naturally very smart. When levels of 1,25(OH)2D3 increase, production of PTHrP is decreased, thus protecting us against an overload of calcium circulating in the bloodstream (a potentially fatal condition called hypercalcemia).² However, if PTHrP is being supplied, not by our own internal production, but externally by a drug, abaloparatide, this natural safety mechanism is circumvented, potentially increasing risk of hypercalcemia.
Furthermore, PTHrP is also secreted by cancerous tumors. When a tumor secretes PTHrP, this can lead to hypercalcemia, and in fact, hypercalcemia caused by tumor-secreted PTHrP binding to PTH1R is a well-known early indicator of malignancy. ³⁻⁴
If chronically elevated, either PTH or PTHrP will cause bone loss because, as mentioned above, when blood levels of calcium drop too low, PTH and PTHrP increase osteoclast activity, so calcium will be released from bone to increase calcium levels in the blood. However, if blood levels of PTH or PTHrP are elevated intermittently—which is what once daily injections of teriparatide (or abaloparatide) are supposed to do, osteoblasts get activated more than osteoclasts, so the hoped for net effect is more bone-building than bone-removal activity.
More specifically, in bone, the PTH1R receptor is found on the surface of osteoblasts, and when it is activated through PTH binding, osteoblasts are activated and start to build bone, but these osteoblasts then also produce a signaling agent called RANKL (Receptor Activator of Nuclear Factor Kappa B Ligand). RANKL’s job is to bind to a receptor on osteoclasts called RANK (the Receptor Activator of Nuclear Factor Kappa B). This binding of RANKL to RANK activates osteoclasts, the specialized cells that break down worn out or damaged bone, so they can clear out the old bone to make room for the new, healthy bone the osteoblasts are building.
Okay, bear with me – there’s one more step in this process you need to know to understand the difference between teriparatide and abaloparatide.
The PTH1R receptor appears in two different versions on our osteoblasts: R(0) and RG. Binding to R(0, which is what teriparatide prefers to do, activates the calcium-regulating system for a longer duration than binding to RG, which is what abaloparatide prefers. A longer duration of PTH1R signaling results in a fairly comparable amount of both osteoblast and osteoclast activation. Shorter duration of PTH1R signaling results in osteoclasts being activated a bit less.
Studies in animals had suggested that abaloparatide — because of its shorter signaling duration — could stimulate bone formation with less of the accompanying osteoclast activation and bone resorption, and less hypercalcemia than teriparatide.¹
So, it sounded like abaloparatide might do a much better job than teriparatide. However, the results seen in the recently published JAMA study don’t show enough of a difference between the two drugs to justify calling abaloparatide significantly better. But the most important reason abaloparatide is not our bones’ dream-come-true is that abaloparatide causes the same adverse effects as teriparatide.⁵
18-month Increases in BMD Seen with Abaloparatide Compared to Teriparatide
Abaloparatide group: BMD at Total hip +3.52%, Femoral neck BMD +3.34%, Lumbar spine +8.72%
Teriparatide group: BMD at Total hip BMD +3.26%, Femoral Neck + 2.66, Lumbar spine +10.49%
Abaloparatide’s main benefit over teriparatide appears to be that it causes a bit less immediate hypercalcemia (discussed below along with all the other adverse effects these drugs can produce) after being injected than does teriparatide. Funny how, now that abaloparatide is the new drug on the block, they’re admitting that teriparatide significantly increases risk for hypercalcemia – and saying alaloparatide is better because it increases this risk a bit less.
As shown above (18-month Increases in BMD seen with Abaloparatide compared to Teriparatide), abaloparatide does appear to increase BMD in some areas a bit more than teriparatide, but in others, particularly the lumbar spine, teriparatide does better, so it’s a bit of a washout.
Abaloparatide’s (supposedly better) BMD outcome is due to its more selective binding to the RG ligand on the PTH1R (PTH receptor type 1) instead of the RO ligand. As explained above, the RG binding releases more rapidly than the RO binding, so you’re supposed to get the anabolic effect of osteoblast activation with less of the RANKL production (osteoclast activation) effect.
These increases in BMD sound lovely (at least if you’re a pharmaceutical rep), but with both drugs, you’re activating parathyroid hormone signaling a lot more than is normal. All the press releases are saying about the resulting adverse effects is that they are “similar” between the two drugs. And frankly, that’s not good. Here’s why:
These drugs’ “undesirable side effects,” include not only nausea, leg cramps and dizziness, but, hypercalcemia (as noted above), plus hypercalciuria, and hyperuricemia – and more.
Teriparatide (and its Cousin, Abaloparatide) Increase Risk for Hypercalcemia, Hypercalciuria, Hyperuricemia
Hypercalcemia = excessively high blood levels of calcium, a very serious condition whose most common cause is abnormal parathyroid gland function.⁶
Hyperuricemia = high levels of uric acid in the blood, a key cause of gout, also of lead toxicity. Hyperuricemia is very harmful to the kidneys, and if uric acid levels are chronically elevated, can cause kidney stones and eventually kidney failure. Since your kidneys are responsible for transforming the form of vitamin D circulating in your bloodstream (25[OH]D) into vitamin D’s active hormonal form of 1,25-D (the form in which vitamin D helps you absorb calcium), taking a drug that harms your kidneys is not going to help you build bone long-term.
Hypomagnesia = low blood levels of magnesium. Hypomagnesia is not the equivalent of magnesium deficiency and can be present without it, although hypomagnesia typically indicates systemic magnesium insufficiency. Symptoms include: weakness, muscle cramps, cardiac arrhythmia, increased irritability of the nervous system, and plenty more. Plus, magnesium is an essential ingredient in healthy bones:
- 60% of the magnesium in the human body is found in bone where it is a key constituent of the bone matrix and is required for osteoblast production, development and activity.
- Magnesium is also the co-factor for the enzyme in the kidneys that converts 25(OH)D to 1,25-D; no magnesium and this enzyme doesn’t work. And that means, you don’t absorb calcium effectively.
- And the majority of Americans are already magnesium-deficient – without the help of teriparatide or abaloparatide.
- Americans of all ages consume less magnesium than their respective EARs (Estimated Average Requirement). The EAR is the amount thought to be “adequate,” not optimal, for only half (50%) of us. 55% of women and 58% of men aged 51-70 years, and 70% of women and 80% of men over age 70 are not even meeting the EAR.
- Magnesium insufficiency results in a full out raid on your bones by Gang Inflammation: highly damaging free radicals (e.g. peroxynitrite, super oxide), pro-inflammatory prostaglandins (PGE2 series), substance P, C-reactive protein, TNFα, all increase, activate osteoclasts and destroy bone.
In research evaluating the effects of teriparatide, in the first month of drug “therapy,” hypercalcemia was noted in 5.5% of study subjects; hyperuricemia was seen in 54.56%, and hypomagnesia in 43%. By the end of the sixth month, these adverse effects continued to occur in 1.38%, 8.77% and 5.5% respectively—not nearly as alarming, but still far too frequent to discount — because all harm bone, and all can be life-threatening. ⁷
Teriparatide (and its Cousin, Abaloparatide) May Increase Risk for Bone Cancer
Because osteogenic sarcoma (a very aggressive bone cancer) occurred in almost half the animals in the rat studies conducted to test teriparatide’s safety and efficacy, the drug comes with an FDA “black-box” warning about this potential long-term side effect.⁸
It’s true teriparatide has been linked to few cases of bone cancer so far, but this drug only received FDA approval for use (for a maximum of 24 months) in postmenopausal osteoporosis and glucocorticoid-caused osteoporosis in 2010, and cancer takes many years to develop. The vast majority of malignancies do not produce symptoms for years, sometimes decades.⁹⁻¹⁰
It is important to not only recall that in the animal studies, long-term treatment with teriparatide (20 months) caused bone cancer in almost half the animals, but also to note that the studies run to evaluate teriparatide’s effects on humans to date have been short-term, a maximum of 36 months. The rats fared much better when a very low dose was used and “treatment” began when they were quite young, just 6 months old, so the human equivalent of a teenager.¹¹ Are you inspired to start your teenager on super low dose teriparatide? Bottom line: No one has any real idea of whether the people who have been given teriparatide, even short-term, will later develop bone cancer as a result.
The recent JAMA study comparing abaloparatide to teriparatide ran for just 18 months. And in the recruitment phase of this JAMA study, anyone with a history of bone cancer was excluded from participation. Obviously, the researchers felt abaloparatide might increase risk for osteosarcoma, especially in susceptible individuals.
Let me remind you that abaloparatide is a made-in-the-lab copy of the first 34 amino acids in PTHrP, and PTHrP is secreted by cancerous tumors, leading to hypercalcemia, for which reason, hypercalcemia is a red flag that the patient needs to be evaluated for malignancy.
You won’t see this potential long-term increased risk for cancer mentioned in any of the press releases about abaloparatide. And there’s no mention of potential increased risk of cancer in the JAMA article itself – it’s only indirectly noted in the “Supplementary Online Content,” which very few people read. I do.
And it’s apparent that the folks who designed the JAMA study certainly know about it. Included in the LONG list of reasons for excluding people from participating in the study are two related to cancer:
- History of any cancer within the past 5 years (other than basal cell or squamous cancer of the skin).
- History of osteosarcoma at any time.
Teriparatide (and its Cousin, Abaloparatide) Increase Cortisol Levels
Teriparatide has been found to increase blood and urine levels of the stress hormone, cortisol when given to postmenopausal women with osteoporosis. The women’s cortisol levels had increased above baseline after just 6 months of teriparatide treatment (with the standard dose of 20 micrograms self-administered by injection daily). After 12 months, the increase in cortisol levels was significant.
This is not surprising since teriparatide causes a spike in parathyroid hormone levels, and one of parathyroid hormone’s effects is to increase the adrenal glands’ secretion of cortisol.¹²
Cortisol is our body’s own premier natural glucocorticoid. Chronic exposure to high levels of glucocorticoids kills osteocytes (the kind of cells that osteoblasts become once they begin building the bone matrix). Even “subclinical” elevations in cortisol levels (an increase in cortisol levels small enough to cause no noticeable symptoms) is associated with increased occurrence of osteoporosis and vertebral fractures—and high blood pressure, type 2 diabetes, high cholesterol, and central obesity (the unhealthiest type of obesity in which inflammatory fat deposits are concentrated around the abdominal organs).¹³⁻¹⁶
Teriparatide (and its Cousin, Abaloparatide) May Promote Cognitive Decline and Dementia (Alzheimer’s)
Need one more reason why it may not be a good idea to abnormally boost your PTH or PTHrP levels every day? Above normal levels of PTH are associated with cognitive decline and dementia (Alzheimer’s).
In 2000, an animal study published in the British Journal of Pharmacology reported that an active fragment of PTH (PTH 1-34, i.e., teriparatide) caused significant brain toxicity within one week. In contrast, PTHrP 1-34, i.e. abaloparatide, did not – in this one week study. The researchers suggested that chronically high levels of PTH may cause brain toxicity by causing calcium overloading in the brain, which results in brain degeneration.¹⁷
In 2010, a 10-year longitudinal prospective study was published that included 514 individuals, ranging in age from 75 to 85 years. Study participants were assessed using the Mini-Mental State Examination (MMSE) and Clinical Dementia Rating (CDR) at baseline and at intervals of one, five and ten years. Elevated PTH indicated a 220% increased risk of an at least 4-point decrease in MMSE and a 300% risk of an increase in CDR-class within the first year of follow- up. The risk remained significantly elevated even after controlling for age, gender, baseline cognition, serum Ca2+ (blood levels of calcium), creatinine (a byproduct of muscle metabolism that is excreted in urine and serves as an indicator of kidney function), and APOE4 (a genetically inherited version of a lipoprotein that carries cholesterol throughout the body, APOE4 is a risk factor for dementia).¹⁸
In 2015, a systematic review and meta-analysis of 27 studies looking at the association between elevated PTH, cognitive function and dementia, provided further evidence of a link between higher blood levels of PTH and poor cognition.¹⁹
The connection – in rats and humans — is that chronic elevation of PTH in the brain increases risk of calcium overloading, which leads to impaired blood flow in the brain and brain degeneration.²⁰ Interestingly, when PTH activity is excessive, the human body tries to inhibit PTH production in two ways: by increasing blood levels of calcium and decreasing blood levels of magnesium. Not surprisingly, both hypercalcemia and hypomagnesia are seen in response to teriparatide, and since abaloparatide is already admitted to cause the same ADRs, will be seen in response to this “new and improved” PTH1R signaling booster as well.
Teriparatide’s Ability to Stimulate Bone Formation Begins to Drop Off after 6 to 12 Months
Teriparatide’s dramatic stimulation of bone formation peaks at 6 to 12 months, after which bone remodeling markers in serum (i.e., s-P1NP [procollagen type 1 amino-terminal pro-peptide], a marker of bone formation, and NTx, [type I collagen N-telopeptide], a marker of bone resorption) drop back down to baseline levels, as shown in the graphs below. This waning of osteoblast stimulation may be one of the limiting factors in the clinical use of teriparatide, although the mechanisms underlying this effect remain unknown.
Graph: Time-dependent changes in skeletal response to teriparatide: escalating vs. constant dose teriparatide (PTH 1-34) in osteoporotic women.²¹
And Bone Formation Appears to Drop Off Even More Rapidly with Abaloparatide
In the JAMA study, the bone formation marker s-PINP and the bone breakdown marker s-CTX (serum collagen type 1 cross-linked C-telopeptide, a comparable marker to NTx), both showed significant increases in study participants given either abaloparatide or teriparatide. But after a few months, bone formation dropped off even more quickly in those treated with abaloparatide compared to teriparatide recipients.
Initial increases in the bone formation marker s-PINP were similar for abaloparatide and teriparatide for the first month, but by 3 months, s-PINP (bone formation) began to decrease in the abaloparatide group compared with the teriparatide group. On the other hand, the increase seen in the bone resorption marker, s-CTX, was also less in the abaloparatide group than in the teriparatide group.
What does this mean overall? Abaloparatide caused less new bone formation than teriparatide, but also resulted in less old bone removal than teriparatide. The question is—is this a good thing? Who knows if it will be helpful long-term.
We do know that we need to remove old bone to make room for its replacement by new bone. Preventing this from happening is one of the main reasons why the anti-resorptive drugs, the bisphosphonates and denosumab eventually cause fractures by retaining old, worn out, brittle bone.
The more I’ve learned over the last 25 years about the intricate symphonic balancing act required for healthy bone remodeling, which involves dozens of molecular actors working in harmony and numerous feedback loops, the more ludicrous – and frightening — I find reductionistic attempts to manipulate this process with man-made fragments of PTH or PTHrP (or the anti-resorptive drugs that prevent normal osteoclast activity—the bisphosphonates and denosumab).
Not surprisingly, all of these simple-minded approaches result in numerous unhappy outcomes.
JAMA Study: Adverse Events in Subjects Given Abaloparatide, Teriparatide and Placebo
|Miller et al., JAMA Study, 2016|
|Adverse event||Abaloparatide (n*=822)||Teriparatide (n=818)||Placebo (n=820)|
|ADRs causing stopping Tx**||81||56||50|
|# of subjects who stopped Tx & quit the study||218||160||184|
|Hypercalcemia (high blood calcium)||28 of 820 subjects||52 of 816 subjects||3 of 817 subjects|
|Hypercalciuria (high urine calcium)||93||102||74|
|High Blood Pressure||59||41||54|
|Urinary tract infection||43||41||38|
|Neoplasms (abnormal cell growth) benign & malignant(cancer)||20||39||29|
This information is presented in Table 3. Safety and Adverse Events.⁵
*n= the number of participants in the group
**Tx = treatment
**Orthostatic hypotension is a form of low blood pressure in which a person’s blood pressure falls when suddenly standing up or stretching
As you can see from the above Adverse Events table, there were more adverse events leading to study discontinuation in the abaloparatide group than in either the teriparatide or placebo groups. In the Abaloparatide group, there were 81 ADRs leading to “discontinuation of the drug” versus 56 in the teriparatide group and 50 in the placebo group.
Adverse events that most often led to study drug discontinuation in the abaloparatide group were nausea, dizziness, headache, and palpitations, which are described as “generally mild to moderate in severity,” meaning some were severe. Serious adverse events leading to discontinuation appeared to occur at similar rates in the abaloparatide and teriparatide groups and with greater frequency than in the placebo group. In other words, both drugs caused serious ADRs — and this was just an 18-month study.
I guessed the leading ADR in the placebo group was constipation because all study participants were given calcium + vitamin D, but NO magnesium. Vitamin D helps us absorb calcium, and calcium causes things to contract, including the lining of our colon. So, calcium + vitamin D, but NO magnesium = contract-> contract-> contract, without relax. Relax = what peristalsis [the contraction + relaxation of muscles that propels food down through and out of the digestive tract] requires — and magnesium delivers. In other words, these folks were set up to develop an uptight, constipated colon. Sure enough, the two highest reasons for “discontinuation of the drug” reported in the JAMA study were constipation & high blood pressure, which is another indication of low magnesium status. 22-23
Let’s suppose you decide to take teriparatide (or abaloparatide when it has official FDA approval) anyway. And let’s further suppose you manage to escape all of its potential adverse effects. Teriparatide is approved for use for a maximum of 24 months (check out the prescribing information).
And it seems likely that the same 24-month maximum duration of use will be mandated for abaloparatide since it has the same potential ADRs as teriparatide. Hopefully, you are going to need your bones for quite a bit longer than 2 more years. Then what do you do?
You’re sure to see lots of glowing press releases telling you how wonderful abaloparatide is, and how much better it is than teriparatide. HealthDay has already published a press release on the JAMA study entitled:
Take an educated look at this press release. Now that you have the facts, you may even be amused by the way they carefully cite the statistics that suggest the new drug is better and fail to report those that show it makes little difference or is worse.
I was heartened by the admission that both drugs cause hypercalcemia, and that it is a real concern: “Hypercalcemia can weaken bones, cause kidney stones and interfere with heart and brain function.”
And was especially entertained by Miller’s comment that abaloparatide will lower patient costs by competing with teriparatide: “I am hoping that having a second drug available, that it will help reduce the cost,” he said. “(Teriparatide) costs about $2,500 a month if you don’t have insurance.” Even if a patient is insured, monthly copays can range from $30 to $400. (Teriparatide) is covered by Medicare, Miller said.
He’s got to be kidding. Cost for teriparatide may drop, but abaloparatide, which doctors will be prescribing as soon as it gets FDA approval, will just cost at least as much, possibly even more than teriparatide.
One last comment in response to statements about bone quality attributed to Miller in the Medline press release: “Abaloparatide and (teriparatide) are synthetic peptides that help grow and strengthen bone. Along with building bone density, they are the only ones that increase bone quality, he said. “Bone quality is an important aspect of bone strength — the ability to withstand a break,” Miller said.
Why he claims either drug improves bone quality is a big question. The JAMA study researchers did not check for anything related to bone quality, just BMD and the bone remodeling markers, s-PINP and CTx. They did not evaluate study participants’ bone quality by having them run a greyscale DXA and using it to determine their Trabecular Bone Score (TBS). DXA only reports BMD. TBS tells you about the structural condition of the bone microarchitecture, i.e., about bone quality. So, on what data from the JAMA study is Miller basing his clam?
Don’t be misled. Just because teriparatide and abaloparatide have a short-term anabolic effect, it does not mean that the bone that gets built is strong, healthy bone! You cannot build strong, healthy bone without adequate amounts of all the nutrients our bones require, and, with the exception of calcium, the JAMA study participants were not getting them.
Average daily calcium dosages were adequate: 955 mg in the abaloparatide group, 894 mg in the teriparatide group, and 986 mg in the placebo group. But, the JAMA study participants were not getting sufficient vitamin D3. The entry requirement to participate in the study was a blood level of 25(OH)D of just 15 ng/mL, which indicates severe vitamin D deficiency. Below 20 ng/mL = deficiency. Below 30 ng/mL = insufficiency. Optimal = 50-80 ng/mL. During the study, the daily dosages of vitamin D taken averaged 723 IU in the abaloparatide group, 625 IU in the teriparatide group, and 613 IU in the placebo group. Most people require at least 2,000 IU of vitamin D3 daily to get their blood level of 25(OH)D up to above 30 ng/mL.
And, study participants were not given vitamin K2, magnesium, vitamin C, boron or any of the other numerous trace minerals our bones require to rebuild healthfully.
An editorial accompanying the study in JAMA warned:
“The bar is high for any preventive treatment — in the efforts to prevent a fracture that may or may not ever occur, prescribers do not want to prescribe a therapy that causes a new problem. The way forward for fracture prevention involves not only the development of better therapies . . . and easier delivery systems, but also improved adoption of existing osteoporosis therapies for patients with prior fractures and minimization of adverse effects, particularly those associated with long-term use.”
I certainly agree with these statements. The best – and only truly effective – therapy for osteoporosis, prevention and reversal, is to:
- Identify and eliminate or at least minimize the factors in your diet and lifestyle that promote the chronic inflammation that excessively activates osteoclasts, and
- Supply your bones with all the key nutrients they must have to continuously, beautifully rebuild themselves: calcium, vitamin D3, vitamin K2, magnesium, vitamin C, boron plus numerous other trace minerals, and the omega-3 fatty acids, EPA and DHA.
Let us know what you think in the comments below.
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