Table 1.

Diseases associated with PTHR1 signalling

Disease	Biological cause*	Physiological manifestation	Current treatment	Prospective treatment
Blomstrand’s lethal chondroplasia85	Abrogation of PTHR1 function by homozygous mutation in PTHR1 (Pro132Leu or nonsense mutation)	Advanced endochondral bone formation Prenatal mortality	None	None
Ollier’s disease86	Heterozygous expression of inactive PTHR1 variants (Arg150Cys and other variants)	Development of cartilaginous lesions and tumours in and around bone	None	None
Familial primary failure of tooth eruption87	Heterozygous expression of inactive PTHR1 variants (Pro132Leu, Arg174Cys and other variants)	Premature ceasing of posterior tooth eruption in children and adolescents	None	None
Jansen’s metaphyseal chondroplasia88,89	Constitutive cAMP signalling at PTHR1 from heterozygous mutation in PTHR1 which yields receptor variants with mutations in transmembrane helices 2, 6 or 7 (His223Arg, Thr410Pro or Ile458Arg, respectively)	Short limbed dwarfism Hypercalcaemia Hypophosphataemia	None	Inverse agonists of constitutive PTHR1 signalling38,91
Eiken syndrome90	Alteration in PTHR1 function by homozygous nonsense mutation in PTHR1 (Arg485stop)	Retarded ossification Epiphyseal dysplasia	None	Inverse agonists of constitutive PTHR1 signalling38,91
Primary hyperparathyroidism92	Oversecretion of PTH by parathyroid glands causes excessive PTHR1 activation	Hypercalcaemia Kidney stones	Surgical removal of offending PTH gland	Competitive antagonists of PTHR1 signalling97,98
Humoral hypercalcaemia of malignancy93	Oversecretion of PTHrP by cancer cells causes excessive PTHR1 activation (observed in 20–30% of patients with cancer)	Hypercalcaemia Cachexia	Bisphosphonates Denosumab in bisphosphonate-resistant cases	Neutralizing PTHrP antibodies94–96 Competitive PTHR1 antagonists
Brachydactyl type E99	Heterozygous mutation of PTHLH resulting in expression of PTHrP variants (Leu44Pro and Leu60Pro, corresponding to positions 8 and 24 of mature PTHrP) with reduced activity	Short metacarpals and metatarsals resulting in small hands and feet	None	None
Hypoparathyroidism100–103	Surgical damage to or removal of parathyroid glands, mutation in calcium sensing receptor expressed on parathyroid glands, defective PTH precursor processing	Hypocalcaemia Tetany Numbness	Oral calcium Vitamin D Daily PTH (can be administered separately or together)	Long-acting PTH derivatives62,63,104
Osteoporosis105–107,111,112	Imbalance between bone resorption and bone building processes	Reduction in BMD, alterations in skeletal architecture and increased fracture frequency	Bisphosphonates Denosumab PTH	Analogues of PTHR1 ligands with weak calcium mobilization activity (PTHrP, abaloparatide)112,115

^*Mutation or ligand.

Abbreviations: BMD, bone mineral density; PTH, parathyroid hormone; PTHR1, PTH/PTHrP type 1 receptor; PTHrP, parathyroid hormone-related protein.