H05: Calcium homeostasis
H05 holds parathyroid hormones and analogues (H05A) and anti-parathyroid agents (H05B), which include the calcitonins (H05BA) and cinacalcet (H05BX01) [1].
How do calcium homeostasis drugs work?
The parathyroid hormone analogues teriparatide (H05AA02) and abaloparatide (H05AA04) both bind to and activate the parathyroid hormone (PTH) type 1 receptor. Teriparatide is a 34-amino-acid fragment, identical in sequence to the first 34 amino acids of human PTH, while abaloparatide is identical to PTH-related peptide through its first 22 residues. Abaloparatide appears to favor a transient, more anabolic configuration of the receptor than teriparatide does. The bone-building (osteoanabolic) actions of PTH come directly from its effects on cells of the bone-forming (osteoblast) lineage, and indirectly from stimulating insulin-like growth factor I (IGF-I) synthesis and suppressing sclerostin [2].
The calcimimetic cinacalcet lowers PTH directly. The calcium-sensing receptor on the chief cells of the parathyroid gland is the principal regulator of PTH secretion, and cinacalcet increases its sensitivity to extracellular calcium [3].
Efficacy
In osteoporosis, the endpoints are fractures and bone mineral density (BMD). Teriparatide and abaloparatide both reduce the risk of spine (vertebral) and non-vertebral fractures. They are given for at most 24 months, followed by a drug that slows bone breakdown (an antiresorptive) to maintain the gain in BMD [2].
Between the dose and BMD sit clinical markers: serum calcium, PTH and bone turnover markers. Linking them to BMD motivated a quantitative systems pharmacology (QSP) model of calcium homeostasis and bone remodeling, built around keeping calcium within its narrow physiological range. FDA reviewers used an open-source version of this model to evaluate dosing regimens of recombinant human PTH, rhPTH(1-84), which is parathyroid hormone (H05AA03) given to replace the endogenous hormone in an underactive parathyroid (hypoparathyroidism) [4]. Model-based work in metabolic bone disease ranges from simple pharmacokinetic models to such systems models, with examples from bisphosphonates, denosumab, teriparatide and the sclerostin inhibitors [5].
For cinacalcet in an overactive parathyroid driven by another condition (secondary hyperparathyroidism), the response measured is plasma PTH, which moves inversely with cinacalcet concentration. PTH is highest just before the next dose and lowest about 2 to 3 hours after it [6].
Safety
In patients with normal calcium, teriparatide causes slight, transient rises in serum calcium that peak 4 to 6 hours after the injection and return to baseline by 16 to 24 hours. High blood calcium (hypercalcemia) above 2.76 mmol/L is listed as an uncommon adverse reaction. The most commonly reported adverse reactions are nausea, pain in limb, headache and dizziness. Rats given near-lifetime daily injections developed more bone cancer (osteosarcoma), so treatment should not exceed 24 months. No osteosarcomas have been seen in clinical trials or in post-treatment follow-up [7]. For rhPTH(1-84), the FDA reviewers concluded from their simulations that the dose regimen should be further optimized to address safety concerns about too much calcium in the urine (hypercalciuria) [4].
With cinacalcet, serum calcium falls along with PTH, and the most commonly reported adverse reactions are nausea and vomiting. Cinacalcet is also a strong inhibitor of CYP2D6 [3].