Bone and Calcium Agents

The parathyroid glands secrete PTH when blood calcium is low, and rising calcium shuts secretion off by negative feedback. In bone, PTH releases calcium indirectly through osteoclasts: it stimulates osteoblasts to express RANKL and inhibits osteoprotegerin, which favors osteoclast formation. In the kidney, PTH directly increases calcium reabsorption in the distal tubule and collecting duct, decreases phosphate reabsorption in the proximal tubule, and stimulates 1-alpha-hydroxylase, which makes active vitamin D (calcitriol); active vitamin D in turn drives calcium absorption from the small intestine.

Continuous exposure to PTH, as in hyperparathyroidism, makes bone undergo resorption more than formation; intermittent exposure, as with teriparatide injections, induces formation more than resorption. Teriparatide (PTH 1-34) binds the PTH type 1 receptor, a G protein–coupled receptor on osteoblasts, osteocytes and renal tubular cells; Gs activates adenylate cyclase and cAMP activates protein kinase A, the pathway used for both its anabolic and catabolic effects. The anabolic effect comes from pro-osteoblast growth factors (IGF-1, FGF-2), lower synthesis of the Wnt antagonist sclerostin, and more Runx2 activity, which raise osteoblast survival and number; the catabolic effect comes from RANKL and macrophage colony-stimulating factor. Antiresorptives, by contrast, also reduce formation, because resorption and formation are tightly coupled.

Abaloparatide, a PTHrP analog, is a selective PTH1R agonist that binds the RG conformation of the receptor more than the R0 conformation, producing a brief rise in cAMP while keeping osteoclast resorption low — which is why it is less likely than teriparatide to cause hypercalcemia. Both analogs raise serum calcium. An increase in osteosarcoma was seen in rats given teriparatide, so the labels avoid both drugs in patients at higher baseline risk (open epiphyses, Paget disease, bone metastases, skeletal radiation). Teriparatide is used for more than 2 years of a lifetime only if fracture risk remains high, and abaloparatide beyond 2 years is not recommended.

Sclerostin is an osteocyte-derived glycoprotein that binds LRP5 and LRP6 and prevents activation of the Wnt/β-catenin pathway that normally stimulates osteoblasts; it also increases RANKL and suppresses osteoprotegerin. Romosozumab, a humanized monoclonal antibody, binds and inhibits sclerostin, so it increases bone formation and, to a lesser extent, decreases resorption. Its use is limited to 12 monthly doses, followed by an antiresorptive if needed. It carries a boxed warning that it may increase the risk of myocardial infarction, stroke and cardiovascular death; it is not started within a year of either and is stopped if one occurs.

Denosumab is a fully human IgG2 monoclonal antibody that binds RANKL and competitively blocks it from binding RANK. RANKL normally drives osteoclast differentiation and prolongs osteoclast survival, so blocking it prevents pre-osteoclast differentiation, promotes osteoclast apoptosis and suppresses bone resorption. The effect is not stored in bone: bone-turnover markers reverse if a dose is delayed, and denosumab is not stopped without a following antiresorptive (such as a bisphosphonate) to control a rebound in bone turnover — the label reports multiple vertebral fractures after Prolia is discontinued.

Denosumab undergoes minimal renal filtration and excretion, so it is not dose-adjusted in kidney disease — but hypocalcemia is the danger there. Prolia carries a boxed warning that patients with advanced chronic kidney disease (eGFR below 30, including dialysis) are at greater risk of severe, sometimes fatal hypocalcemia, especially with chronic kidney disease–mineral bone disorder. Osteonecrosis of the jaw and atypical femoral fractures have also been reported.

Raloxifene binds estrogen receptors and, depending on the recruitment of coactivators and corepressors, activates estrogen pathways in some tissues and blocks them in others. It acts as an estrogen agonist in bone, inhibiting the accelerated resorption of postmenopausal osteoporosis and increasing BMD, and as an estrogen antagonist in breast and uterus — unlike tamoxifen, which is an agonist in the uterus. That profile lets it reduce the risk of invasive breast cancer, but it carries a boxed warning for venous thromboembolism and death from stroke, and its commonest effects include hot flashes and leg cramps.

Calcitonin is made by the thyroid’s parafollicular (C) cells; the salmon peptide used as a drug differs in sequence and is more potent. It acts on a G protein–coupled calcitonin receptor: in bone it makes osteoclasts contract, reducing their motility and resorption, and in the kidney it decreases calcium and phosphate reabsorption. Osteoclasts escape its effect within 24 to 48 hours, so its calcium-lowering effect diminishes over 1 to 2 days. Fracture reduction has not been shown, and a possible association with malignancy limits continued use.

In chronic kidney disease, PTH rises to compensate for low calcium: renal failure brings elevated PTH with decreased calcium and elevated phosphate. Hyperphosphatemia lowers calcium and stimulates FGF-23 and PTH, and FGF-23 inhibits 1-alpha-hydroxylase, so active vitamin D falls; the kidneys of uremic patients cannot adequately synthesize calcitriol. Calcitriol replaces it: it binds vitamin D receptors in intestine, kidney, parathyroid and bone and raises serum calcium. As the most potent vitamin D metabolite, its danger is hypercalcemia and soft-tissue calcification.

The calcium-sensing receptor (CaSR) on parathyroid chief cells is a G protein–coupled receptor that detects small changes in extracellular calcium and suppresses PTH secretion. Cinacalcet, a calcimimetic, increases the CaSR’s sensitivity to calcium, lowering PTH and, with it, serum calcium. Its danger is the opposite of calcitriol’s: hypocalcemia, which can prolong the QT interval and lower the seizure threshold. Over-suppressing PTH with vitamin D analogs or calcimimetics can cause adynamic bone disease, a low-turnover state.