Pharmacology of major drug classes used to treat diabetes, osteoporosis, and syndromes of hormonal excess or deficiency

Drug classes

Osteoporosis pharmacotherapy spans antiresorptive agents (bisphosphonates, denosumab - reducing osteoclast-mediated bone resorption) and anabolic agents (teriparatide, romosozumab - stimulating new bone formation) - sequencing between these classes now follows an evolving evidence base rather than a single fixed order for every patient
Osteoporosis pharmacotherapy is extremely widely used given the high population prevalence of osteoporosis and osteoporotic fracture, with treatment selection increasingly individualised by baseline fracture risk severity

Bisphosphonates bind hydroxyapatite and induce osteoclast apoptosis, reducing bone turnover; denosumab (a RANKL inhibitor monoclonal antibody) blocks osteoclast differentiation/activation - both are antiresorptive but denosumab's effect reverses rapidly on discontinuation, causing a recognised rebound vertebral fracture risk if stopped without transitioning to another agent
Teriparatide (recombinant PTH fragment) and romosozumab (sclerostin inhibitor) both stimulate osteoblast-driven bone formation when given intermittently/short-term, producing larger BMD gains than antiresorptive monotherapy in very-high-risk patients

Anabolic-first sequencing (romosozumab or teriparatide for 1-2 years, followed by a bisphosphonate or denosumab to preserve gains) is now guideline-endorsed (ACP living guideline) for patients with primary osteoporosis at very high fracture risk, reflecting FRAME/ARCH trial evidence that this sequence produces greater fracture risk reduction than starting with antiresorptive therapy alone
For most other patients, bisphosphonates remain reasonable first-line therapy given long track record, oral availability, and cost

Very high fracture risk: anabolic agent (romosozumab or teriparatide) first, followed by antiresorptive (bisphosphonate or denosumab) to consolidate gains
Standard risk: bisphosphonate first-line, with denosumab as an alternative particularly where renal function or adherence favours a less frequent dosing schedule
Denosumab discontinuation must always be followed by a transition agent (typically a bisphosphonate) to prevent rebound vertebral fracture risk - never simply stopped without a planned follow-on

Denosumab discontinuation rebound fracture risk (a critical, frequently tested safety point), bisphosphonate-associated osteonecrosis of the jaw and atypical femoral fracture (rare but relevant long-term risks), anabolic-first sequencing in very-high-risk patients
Denosumab must never be stopped without transitioning immediately to another antiresorptive agent (typically a bisphosphonate) - discontinuation causes a rapid rebound in bone turnover with a recognised risk of multiple vertebral fractures, a specific, serious safety issue distinct from simply losing treatment benefit

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