Aortic stenosis (AS) affects 2–3% of the elderly in developed countries. While the prevalence in younger patients is relatively low (0.2% in the 50- to 59-year group), it increases with age may reach up to 10% in patients aged 80–89 . To date, AS is the largest contributor to deaths due to heart valve disease in high-income countries  and its burden is expected to rise with aging of the population. Therefore, research of risk factors and potential therapeutic models for AS, prior to symptoms requiring valve replacement or implantation, are of a great need.
AS is mainly caused by progressive calcium deposition within the valve leaflets. Previous studies have suggested that osteoporosis and low bone mineral density are independently associated with progression of aortic valve calcification that subsequently may lead to hemodynamically significant AS . Calcified cardiac valves often present osteoblast-like cells and increased expression of bone-specific proteins [4,5]. This calcification process is active and shares some features with bone formation. This association was supported by studies indicating that bisphosphonate treatment is associated with slower progression of mild AS . In addition to preventing bone formation on the aortic valve in the primary stages of osteogenesis, the inhibition of osteoclasts using bisphosphonates may act indirectly through altering levels of vitamin D or parathyroid hormone (PTH).
Human PTH is an 84-amino acid peptide produced by the parathyroid glands and is involved in maintenance of calcium and phosphate homeostasis . It is secreted in response to low serum calcium levels and acts directly to increase the release of calcium from the bone, increase renal tubular calcium reabsorption and enhances intestinal calcium absorption by formation of 1,25-dihydroxyvitamin D. Intermittent treatment with exogenous PTH is associated with increased bone mineral density and decreased vascular calcification. A common intermittent exposure to PTH is teriparatide.
Teriparatide is a recombinant formulation of endogenous PTH, containing a 34 amino acid sequence, which is identical to the N-terminal portion of this hormone. The pharmacologic activity of teriparatide is similar to the physiologic activity of PTH. After subcutaneous injection, PTH analogues are absorbed rapidly. The bioavailability of PTH 1–34 and PTH 1–84 is 95 and 55%, respectively . The half-life after subcutaneous injection for PTH 1–34 is approximately 1 h and that for PTH 1–84 is approximately 2.5 h.
Patient consent for a de-identified case report has been provided.
A 64-year-old Jewish woman in Israel (BMI 24 kg/m2) with osteoporosis documented since 1998 (including arm fracture in 2009), hyperlipidemia and hypothyroidism was treated with levothyroxine sodium 50 µg. Other chronic medications include bisoprolol, ezetimibe, rosuvastatin calcium, losartan potassium, omeprazole and aspirin. Since 2013, the patient was tested 23 times for TSH, all of them with normal range (range 1.55–4.47 mIU/L). Similarly, free-T3 and free-T4 were in normal range. The patient had a mild vitamin D insufficiency 69.0 nmol/L and normal blood pressure (90/55 mmHg), heart rate 57 bpm (as recorded in June 2018).
Between 2010 and March 2018, the patient has undergone eight echocardiograms with an aortic valve pressure gradient ranging between 29 and 39 mmHg, defined as mild AS, with no clear trend of progression. Mean pressure gradient was 19 mmHg (range 16–22) in nine measurements between 2010-3 and 2018, as depicted in Fig. 1. In April 2018, the patient was initiating use of FORTEO (250 µg per 1 ml). In two subsequent echo tests conducted four and seven months after treatment initiation, there was a rapid progression of AS with gradient pressures of 55 and 58 mmHg, respectively. The respective mean pressure gradient was 30 and 36 mmHg. No substantial increase was noted in heart rate or blood pressure levels during observation period.
Here, we report a case of rapid development of mild AS to moderate/severe within a course of several months after initiation of treatment with PTH analogues. To the best of our knowledge, this is the first documented report in humans. Results from animal models are conflicting. An in vivo microCT imaging in mice showed that the aortic calcium content increased in both control and teriparatide treatment groups, and that teriparatide treatment neither reduced nor enhanced the progression of aortic calcification . In contrast, a study in diabetic mice found that human PTH (1–34) suppresses heterotopic vascular osteogenesis and mineral accumulation while simultaneously promoting orthotropic skeletal bone formation .
Inappropriate levels of PTH may lead to an increase in renal resorption of calcium and phosphorus, a greater resorption of bone and an increased synthesis of 1,25-dihroxyvitamin D that in turn augments intestinal calcium absorption. Long standing hypercalcemia has been associated with valvular calcification. In one study  of patients with primary hyperparathyroidism, 54% disclosed evidence of valvular calcification, 46% in the aortic valve and 39% in the mitral valve. Calcification in both the aortic and mitral valves was observed in 25% of patients. While teriparatide has been associated with hypercalcemia, it is unclear if among patients without end-stage renal disease, serum calcium and phosphorus metabolism may contribute to the progression of calcific AS. Moreover, due to its relatively short half-life, with maximum post-dose calcium concentration occurring 4–6 h after administration, hypercalcemia due to teriparatide is transient, and persistent hypercalcemia is rare .
One prospective study among elderly patients  reported an association between AS progression, vitamin D, intact parathyroid hormone (iPTH) and the C-terminal telopeptide of type 1 collagen (CTX)-to-osteocalcin ratio (indicating bone resorption to formation) and their respective influence varied according to the vitamin D status. In patients with normal vitamin D levels, AS progression was associated with a bone resorptive remodeling, whereas in patients with low vitamin D levels, AS progression was associated with iPTH and secondary hyperparathyroidism, especially if mild renal insufficiency was present.
Hypertension can modify the physical examination findings of AS, particularly in the elderly patient. A raised blood pressure may not only mask the exploratory findings of AS, but can also modify the hemodynamic indices used to assess the severity of the disease. Thus, in addition to the above-mentioned mechanisms, teriparatide may also affect gradient pressure through changes in blood pressure .
Intermittent exposure to PTH analogues may be one of the causes of rapid progression of AS. Studies with sizeable populations are required to assess causal relationship between PTH analogues use and progression of AS.
Conflicts of interest
There are no conflicts of interest.
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