Abaloparatide

Abaloparatide is a synthetic 34-amino-acid peptide and an analogue of parathyroid hormone-related peptide, PTHrP (1-34). It shares about 76 percent of its sequence with natural PTHrP (1-34) and only 41 percent with the parathyroid hormone fragment PTH (1-34) that teriparatide is made of. Both act on the same target, the PTH1 receptor. Both belong to the small group of agents that build bone rather than merely slowing its breakdown. It was developed by Radius Health.

As a medicine it is approved for osteoporosis with a high fracture risk: as Tymlos in the US for postmenopausal women and for men, as Eladynos in the EU for postmenopausal women only. There is exactly one clinical dose, 80mcg subcutaneously once a day from a prefilled pen, capped at two years in a lifetime in the US and at 18 months in the EU. Here it ships as a freeze-dried powder in a 3mg vial that you dissolve in bacteriostatic water.

We list abaloparatide as a high-risk product. The reasons are spelled out under side effects: in rat studies it caused bone tumours in a dose- and time-dependent way, just like teriparatide. For some people every injection is followed by palpitations, dizziness and a drop in blood pressure over the next few hours. It is not something to start on a whim.

This information is for research and educational purposes only. No medical advice.

Parathyroid hormone and PTHrP regulate calcium balance and bone remodelling through the PTH1 receptor. Timing is everything: a permanently high level, as in an overactive parathyroid gland, breaks bone down and pushes blood calcium up. A brief pulse once a day instead mainly stimulates the bone-building osteoblasts, while resorption follows later and more weakly. In that window the skeleton gains net new bone, most of all in the spine and hip.

Abaloparatide was designed to keep that pulse especially short. The PTH1 receptor exists in two states: a ligand that binds the so-called R0 conformation keeps the receptor signalling long after the drug has left the blood, while a ligand that prefers the RG conformation produces a short signal. Hattersley and colleagues showed in 2016 that abaloparatide favours the RG form far more than PTH (1-34) does and therefore triggers briefer cAMP responses in cells. That is a plausible explanation for why it built at least as much bone density as teriparatide in the trials, slightly more at the hip, while raising blood calcium less often.

The turnover markers show the pattern in the blood: in the pivotal trial the formation marker PINP rose by about 93 percent after one month and was still 45 percent above baseline at 18 months, whereas the resorption marker CTX rose only 26 percent and was back to baseline by 18 months. The pharmacokinetics fit: after a subcutaneous injection the peak level comes after about half an hour, bioavailability is around 36 percent and the half-life is roughly one hour. Within a few hours the drug is essentially gone, but the bone keeps working.

The list is the same as for other daily peptides, with one addition because of the tiny dose:

• The abaloparatide vial with 3mg of freeze-dried powder
• Bacteriostatic water, 3ml of it for the concentration described below
• U-100 insulin syringes, ideally with half-unit marks or a fine scale
• Alcohol swabs for the vial cap and the skin
• A sealable sharps container for used needles

Because the clinical dose is measured in micrograms, the amount of water decides whether the dose can be read off the syringe at all. With 1ml it would be just under 3 units, which is no longer accurate.

The powder is dissolved in bacteriostatic water. The volume sets the concentration. The 3mg vial holds 3,000mcg. With 3ml of water that gives 1,000mcg per ml, i.e. 1mg per ml. The clinical dose of 80mcg is then 0.08ml, which is 8 units on a U-100 syringe. One vial lasts for 37 doses. For comparison, the approved prefilled pen contains 2,000mcg per ml and delivers 80mcg as 40 microlitres.

With 2ml you would get 1,500mcg per ml, so 80mcg would be 5.3 units, which cannot be drawn accurately. With 1ml it would be 2.7 units. That makes 3ml the only volume here that lands on a clean number. The calculator above shows only the concentration and deliberately no dose steps, because we do not set a dose of our own for abaloparatide (see dosing).

Just add the bac water to the vial, it does not matter whether it hits the powder directly. Then swirl or shake until everything is clear, both are fine. If the solution turns gel-like or lumpy, do not use the vial. Slight cloudiness on its own is not a reason.

In the trials and in the prescribing information abaloparatide is injected subcutaneously into the abdomen, around the navel, once a day at about the same time. Never into muscle and never into a vein.

• Clean the spot with an alcohol swab and let it dry
• Pinch up a small fold of skin and insert the needle at a 45 to 90 degree angle
• Inject, wait a moment, withdraw and put the needle straight into the sharps container
• Rotate the injection site every day

One point that comes straight from the prescribing information: the first injections belong somewhere you can sit or lie down. Within about four hours of an injection blood pressure can drop on standing, with dizziness, palpitations or nausea. Lying down usually settles it. Knowing that, you do not inject right before driving or training.

The pivotal ACTIVE trial (Miller 2016, JAMA) compared 80mcg of abaloparatide daily with placebo and with 20mcg of teriparatide for 18 months in 2,463 postmenopausal women with osteoporosis. New vertebral fractures and fractures outside the spine were less frequent under abaloparatide than under placebo. Bone density rose at the spine, hip and femoral neck. Raised blood calcium occurred in 3.4 percent under abaloparatide and 6.4 percent under teriparatide. The extension ACTIVExtend (Bone 2018) then gave both groups 24 months of alendronate: across the full 43 months, 0.9 percent of women after abaloparatide had a new vertebral fracture versus 5.6 percent after placebo, an 84 percent reduction. Hip fractures: none versus five.

In men the ATOM trial (Czerwinski 2022) randomised 228 men with osteoporosis to 80mcg or placebo for 12 months. Lumbar spine density rose 8.5 percent versus 1.2 percent, total hip 2.1 versus 0 percent. The study was too small and too short to count fractures. The dose-finding study (Leder 2015) maps the dose-response curve from 20 to 80mcg. The receptor work (Hattersley 2016) supplies the mechanism behind the shorter signal.

What the research does not show: there are no solid data in people with normal bone density, none beyond two years of use and none in athletes. On fracture healing there is so far only one small trial in 48 older people with pelvic fractures (Nieves 2026). There the fractures did not heal better on abaloparatide than on placebo after three months. That makes the rat carcinogenicity study (Jolette 2017) all the more important; it is covered under side effects. The studies with links are in the source block below.

The biggest issue is the osteosarcoma signal. In the study by Jolette 2017, Fischer rats received 10, 25 or 50mcg per kg of abaloparatide daily for up to two years, or 30mcg per kg of PTH (1-34) as a comparator. Under both substances bone tumours, mostly osteosarcomas, developed in a dose- and time-dependent way, at comparable rates for comparable exposure. According to the prescribing information the rat doses correspond to 4 to 28 times the human exposure at 80mcg. In humans, observational studies of PTH analogues have so far not shown an increased osteosarcoma risk, although individual cases have been reported. That is why the current US label carries the risk as a warning rather than the boxed warning this class used to have. The warning itself remains and so does the two-year limit. The EU allows only 18 months anyway. For anyone with open growth plates, bone metastases or prior radiation to the skeleton, abaloparatide is off limits.

The common side effects from the pivotal trial (abaloparatide versus placebo): increased urinary calcium 11 versus 9 percent, dizziness 10 versus 6, nausea 8 versus 3, headache 8 versus 6, palpitations 5 versus 0.4, fatigue 3 versus 2, upper abdominal pain 3 versus 2. Ten percent stopped because of side effects versus 6 percent under placebo, most often for nausea, dizziness, headache and palpitations. Raised blood calcium occurred in 3.4 percent, half the teriparatide rate but not zero. In men, injection site reactions, dizziness and joint pain led the list.

Heart and circulation: in the first hour after an injection the heart rate rises, by about 8 beats per minute on average after the first dose in the pivotal trial (just over 1 under placebo) and by 15 beats on average, measured 15 minutes after dosing, in the cardiac rhythm study in healthy volunteers. Blood pressure drops slightly at the same time. About 1 percent had orthostatic hypotension with dizziness. It is usually over after roughly four hours, although in some people the faster pulse lasted up to six hours. In a dedicated cardiovascular analysis of the pivotal trial serious cardiac events were no more frequent than under placebo. Even so, the EU label asks for a check of blood pressure, heart and ECG before the start and for the first injection to be given under medical supervision. And in practice: do not inject and then get on the bike. Add hypersensitivity reactions up to anaphylaxis (rare, but reported) and the risk of kidney stones with increased urinary calcium.

Bottom line: abaloparatide is a highly effective medicine for a clearly defined purpose, with a cancer signal from animal studies, a hard time limit and a circulatory effect right after every injection. That is why it is classed as a high-risk product.

The undissolved powder is robust: stored at room temperature, dark and dry, it keeps for several months, no fridge needed. The approved prefilled pen is also refrigerated before first use and may then sit at room temperature for 30 days, which shows the molecule is more robust in solution than you might expect from a PTH analogue.

Once dissolved, the solution goes into the fridge and keeps for several months there; the bacteriostatic water brings a preservative with it. At 80mcg a day a 3mg vial is empty after about five weeks anyway, so shelf life is not the bottleneck. Do not freeze and do not leave it in the sun. If the solution turns gel-like or lumpy, do not use the vial. Slight cloudiness on its own is not a reason.