Tymlos is a unique form of parathyroid hormone therapy for osteoporosis. It is called PTHrp and we think it its physiologic role is primarily in the life of very young even fetal life during rapid bone growth and modeling. It increases bone formation without first increasing bones reabsorption. In the young, bone removal is needed only to the extent that it needs to be modeled not because it is effete and must been replaced. This feature of Tymlos results in outsized increases in bone mass and density with its use compared with Forteo when it was used together in an open label comparator study. This differential effect over Forteo was most apparent in the hip’s femoral neck DXA measurement site.
Indications and Usage for Tymlos from the Label
TYMLOS is indicated for the treatment of postmenopausal women with osteoporosis at high risk for fracture defined as a history of osteoporotic fracture, multiple risk factors for fracture, or patients who have failed or are intolerant to other available osteoporosis therapy. In postmenopausal women with osteoporosis, TYMLOS reduces the risk of vertebral fractures and nonvertebral fractures.
Efficacy Study in Women with Postmenopausal Osteoporosis
Treatment of postmenopausal osteoporosis was evaluated in an 18-month, study of 1645 postmenopausal women with osteoporosis whose average age were 69, and 80% were white. 24% had vertebral fractures at the beginning of the study. All subjects received calcium and vitamin D for the 18 month study duration.
The new vertebral fracture rate in the placebo treated subjects was 42 in 1,000 vs. 6 in 1,000 fractures in the Tymlos group representing a 86% statistically significant relative risk reduction and a 3.6% absolute risk reduction. To prevent 1 new vertebral fracture in women like those in the study would require treatment of 28 women for 28 days.
The study was too small to look a hip fracture risk.
In the peripheral skeleton that included the hip and wrist the in the placebo group relative risk reduction was 43% with a fracture rate of 47 per 1,000 vs. 27 per 1,000 on the Tymlos subjects. The absolute risk reduction was a statistically significant 2%. To prevent 1 peripheral fracture requires treating 50 women like those in the study for 18 months.
Bone density increased 9.2% in the spine, 3.4% in the total hip and 2.7 in the femoral neck.
Limitations of Use
Because of the unknown relevance of the rodent osteosarcoma findings to humans, cumulative use of TYMLOS and parathyroid hormone analogs (e.g., teriparatide) for more than 2 years during a patient’s lifetime is not recommended
- Orthostatic Hypotension low blood pressure can occur within 4 hours of the injection. Associated symptoms may include dizziness, palpitations, tachycardia, or nausea. Lying down helps. Taking the medication before bed helps.
- Hypercalcemia TYMLOS naturally raises the serum calcium. This is expected to happen and is not a concern. Drink plenty of water when using Tymlos.
- Hypercalciuria and Urolithiasis TYMLOS causes increased calcium in the urine and could cause kidney stones in some people. Drink plenty of water when taking Tymlos as this helps dilute the calcium in the urine and prevent kidney stones. This is a rare side effect.
Warnings and Precautions
Risk of Osteosarcoma
Abaloparatide caused a dose-dependent increase in the incidence of osteosarcoma in male and female rats after subcutaneous administration at exposures 4 to 28 times the human exposure at the clinical dose of 80 mcg. It is unknown whether TYMLOS will cause osteosarcoma in humans. The use of TYMLOS is not recommended in patients at increased risk of osteosarcoma including those with Paget’s disease of bone or unexplained elevations of alkaline phosphatase, open epiphyses, bone metastases or skeletal malignancies, hereditary disorders predisposing to osteosarcoma, or prior external beam or implant radiation therapy involving the skeleton. Cumulative use of TYMLOS and parathyroid hormone analogs (e.g., teriparatide) for more than 2 years during a patient’s lifetime is not recommended.
This warning has become standard boilerplate now for this and all PTH-like drugs. So far, they have all triggered osteogenic sarcoma in the Fisher 344 rat that is used by the pharmaceutical companies at the direction of the US FDA to test these agents. The fact that over 1,000,000 people worldwide have been treated with 1-34 Teraparatide, a PTH similar to Tymlos and none of these people have experienced osteogenic sarcoma is really interesting. There should have been 50 cases of this rare fatal cancer by chance alone since that drug first came on the market in 2002. So far, there have been no cases. Certainly, the US FDA is aware of this fact. Why do they insist that this warning be placed on this new drug and continue on the Teraparatide label when it is clear that these legitimate fears surrounding this drug when it was first introduced have not manifest?
Tymlos Therapy Compared to Forteo for Osteoporosis
In the registration study described above, what was not mentioned was the inclusion of 818 postmenopausal women who were also enrolled in the study that were randomized to open label Forteo as a comparator to Tymlos and placebo. The subjects in all 3-study groups we studied were the alike in all significant characteristics.
With regard to new vertebral fractures Tymlos and Forteo therapy resulted in statistically significant reductions of similar magnitude. Tymlos however therapy was distinctly superior with respect to prevention of peripheral fractures statistically significant margin. One explanation for Tymlos’ superiority in this regard is hinted at in the bone density data that is displayed below taken from the JAMA article by Miller etal published in 2016.
Mean percent changes in bone mineral density at the total hip, femoral neck, and lumbar spine were evaluated using dual-energy x-ray absorptiometry based on the intent-to-treat population. Values shown are mean percent change from baseline using a mixed-effect repeated-measures model. Improvements in bone mineral density associated with abaloparatide were significantly greater than with placebo at all 3 sites and at all time points (P < .001). Improvements with teriparatide were significantly greater than with placebo at all 3 sites at all time points (P < .001). Improvements with abaloparatide were significantly greater than those with teriparatide at the total hip and femoral neck at all time points (P < .001) and at lumbar spine at 6 and 12 months (P < .001). Error bars indicate 95% CIs.
These data show that Tymlos therapy results in a significantly greater increase in bone density at the total hip and femoral neck sites than seen with Forteo. The peripheral skeleton anatomically resembles the long bones of the femur to a much greater degree than it does the vertebral body. To me, this suggests one possible explanation for Tymlos therapy resulting in a significant reduction in peripheral fractures after only 18 months is because like in the hip, Tymlos’ mechanism of action has a broader skeletal effect than teraparatide. Forteo’s activity appears to be more focused upon skeletal tissues with open architecture like the spine, where it rapidly increased BMD and prevents new vertebral fractures. Tymlos on the other hand is equally active at the spine and the periphery.
I intend to take full advantage of Tymlos therapy to build my osteoporosis patient’s bone mass by using this unique treatment for all 24 months of its US FDA indication. Tymlos therapy restores bone quality in patients with osteoporosis by repairing the damaged infrastructure caused by excessive and prolonged bone remodeling. This therapy implements this repair by calling upon the bodies own mesenchymal and hematologic stem cells to differentiate into osteoblasts, osteocytes, and osteoclasts. These cells compose the basic multicelluar unit that forms new bone tissue adding strength, vigor, and health to the skeleton.