Bone and calcium drugs compared — antiresorptive vs anabolic, and the calcium–PTH drugs

Resorption and formation are tightly coupled, so drugs that inhibit osteoclast-mediated resorption also reduce new bone formation. The antiresorptives act on osteoclasts in different ways: bisphosphonates bind hydroxyapatite and are released into resorbing osteoclasts (the nitrogen-containing agents inhibit farnesyl pyrophosphate synthase); denosumab blocks RANKL; raloxifene acts as an estrogen agonist in bone; and calcitonin makes osteoclasts contract. Alendronate reduces resorption with no direct effect on bone formation.

The anabolics increase formation instead. Continuous PTH, as in hyperparathyroidism, makes bone undergo resorption more than formation, but intermittent exposure to teriparatide or abaloparatide induces formation more than resorption, through the PTH type 1 receptor. Romosozumab inhibits sclerostin, increasing bone formation and, to a lesser extent, decreasing resorption.

Bisphosphonates are incorporated into the bone matrix and released gradually over years — alendronate’s terminal half-life exceeds 10 years — so the labels suggest considering stopping after 3 to 5 years in patients at low risk for fracture. Denosumab is the opposite: its effect is not stored in bone, bone-turnover markers reverse when a dose is delayed, and it is not stopped without a following antiresorptive such as a bisphosphonate, because bone turnover rebounds and multiple vertebral fractures can follow.

The anabolics are time-limited. Romosozumab is limited to 12 monthly doses, after which continued therapy with an antiresorptive is considered; 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.

Bisphosphonates and denosumab share osteonecrosis of the jaw and atypical femur fractures. The boxed warnings differ by drug: denosumab (Prolia) for severe hypocalcemia in advanced chronic kidney disease, romosozumab for myocardial infarction, stroke and cardiovascular death, and raloxifene for venous thromboembolism and death from stroke.

PTH raises serum calcium through bone, kidney and — via 1-alpha-hydroxylase and calcitriol — the gut, and the PTH analogs raise calcium too. Calcitriol, the active vitamin D that uremic kidneys cannot make, raises serum calcium; its danger is hypercalcemia. Cinacalcet works in the other direction: it increases the parathyroid calcium-sensing receptor’s sensitivity to calcium, lowering PTH and serum calcium, and its danger is hypocalcemia, which can prolong the QT interval and lower the seizure threshold.

In hypercalcemia of malignancy, IV normal saline comes first, with IV zoledronic acid (preferred for its potency and shorter infusion) or pamidronate; bisphosphonates begin working in 2 to 3 days, whereas calcitonin acts within 4 to 6 hours but escapes within 24 to 48 hours. Hypocalcemia is a shared risk of the IV bisphosphonates and denosumab.