Treatment of Osteoporosis

Key questions

1. Q1What is osteoporosis?

   A systemic disease of weakened, fragile bone that raises fracture risk. Bone strength = bone density (BMD) + bone quality. It is "silent" until a fracture occurs.
2. Q2What is the goal of treatment?

   Fracture prevention. Raising BMD matters, but the clinical goal is fewer fractures.
3. Q3What happens in normal remodeling?

   Osteoclasts resorb and osteoblasts form bone in coupled units, maintaining skeletal integrity.
4. Q4What is the RANKL/OPG system?

   RANKL (from osteoblasts/stromal cells) binds RANK on osteoclast precursors and osteoclasts → osteoclast formation and activity. OPG (osteoprotegerin) is a decoy receptor that binds RANKL and blocks it.
5. Q5What does sclerostin do?

   An osteocyte-derived protein that inhibits Wnt signaling → acts as a brake on bone formation.
6. Q6What shifts the balance toward osteoporosis?

   Aging, estrogen deficiency, glucocorticoids, PTH excess and other conditions → resorption > formation.
7. Q7Which levers do osteoporosis drugs pull?

   RANKL (denosumab, estrogen), the osteoclast directly (bisphosphonates), the PTH receptor (teriparatide, abaloparatide), the estrogen receptor (estrogen, raloxifene) or sclerostin (romosozumab).
8. Q8What non-drug measures come first?

   Strength/resistance training ≥2 days/week, balance training daily, aerobic exercise; vitamin D ≥1000 IU/day, calcium 1200 mg/day total, protein 1–1.5 g/kg/day → more muscle and bone, fewer falls and fractures.

Key questions

1. Q9What are the two main classes?

   Antiresorptive (anti-remodeling) agents and osteoanabolic agents.
2. Q10What do antiresorptives do?

   Inhibit resorption (more than formation); stabilize or modestly increase BMD; improve strength but do not restore trabecular architecture.
3. Q11Which drugs are antiresorptive?

   Estrogen (± progestin), estrogen/bazedoxifene, raloxifene (estrogen agonist/antagonist), bisphosphonates (alendronate, risedronate, ibandronate, zoledronic acid), denosumab (RANKL inhibitor), calcitonin.
4. Q12What do osteoanabolic agents do?

   Activate bone formation; larger BMD gains; restore microarchitecture.
5. Q13Which anabolics are "remodeling stimulators"?

   PTH receptor agonists — teriparatide (PTH 1-34) and abaloparatide (PTHrP analog). They increase formation AND resorption.
6. Q14Which anabolic has a dual effect?

   Romosozumab (anti-sclerostin): a modeling stimulator that increases formation AND decreases resorption.
7. Q15How do bisphosphonates work?

   They bind hydroxyapatite; osteoclasts take them up during resorption → dysfunction and apoptosis. Nitrogen-containing ones inhibit farnesyl pyrophosphate synthase (mevalonate pathway) → impaired cytoskeleton.
8. Q16How does denosumab work?

   Fully human monoclonal antibody to RANKL → blocks RANKL–RANK binding → inhibits osteoclast differentiation and decreases function/survival of mature osteoclasts.
9. Q17How does intermittent PTH build bone when PTH excess destroys it?

   Key paradox: continuous PTH excess → ↑ resorption; intermittent PTH-receptor stimulation preferentially activates osteoblasts (↓ apoptosis, ↑ differentiation) → anabolic.
10. Q18How does abaloparatide differ from teriparatide?

    PTHrP analog that favors the R0 receptor conformation → optimizes anabolic effect with fewer pro-resorptive effects.
11. Q19What does a bisphosphonate do to the remodeling space?

    It slows bone turnover and shrinks the remodeling space — the bone surface under active resorption at any one time.
12. Q20Are all bisphosphonates equally potent?

    No. Risedronate inhibits osteoclasts more strongly than alendronate or ibandronate.
13. Q21How does estrogen act on the bone cells themselves?

    It speeds osteoclast death (apoptosis) and prolongs osteoblast survival, besides lowering RANKL and raising OPG.

Key questions

1. Q22Bisphosphonates: how are oral forms taken and why?

   With 8 oz plain water on an empty stomach, staying upright afterward — poor GI absorption and risk of esophageal irritation.
2. Q23Bisphosphonate adverse effects?

   Oral: esophagitis, dyspepsia, abdominal discomfort. IV: acute-phase reaction (fever, myalgias, flu-like). Serious/rare: osteonecrosis of the jaw (ONJ), atypical femoral fractures (AFF), hypocalcemia, renal toxicity (especially IV zoledronic acid).
3. Q24Bisphosphonate contraindications?

   Hypocalcemia and reduced renal function (CrCl <30–35 mL/min); oral forms: significant esophageal disease or inability to stay upright.
4. Q25Which bisphosphonate is NOT first line and why?

   Ibandronate — its pivotal trial reduced only vertebral fractures (not hip or non-vertebral). Alendronate, risedronate and zoledronic acid reduce vertebral, non-vertebral and hip fractures.
5. Q26Denosumab indications?

   Postmenopausal women and men at high fracture risk; glucocorticoid-induced osteoporosis; men on androgen deprivation for prostate cancer; women on aromatase inhibitors for breast cancer.
6. Q27Denosumab contraindications and adverse effects?

   Contraindicated: hypocalcemia (correct first), pregnancy, hypersensitivity. Adverse: eczema/rash/dermatitis, skin infection/cellulitis, rare ONJ and AFF.
7. Q28What is the denosumab "kidney paradox"?

   It is not renally cleared (no dose adjustment), but advanced CKD (eGFR <30, dialysis) carries a much greater risk of SEVERE HYPOCALCEMIA — FDA boxed warning.
8. Q29Estrogen: mechanism, best use and contraindications?

   Preserves bone by ↓ RANKL/↑ OPG, ↓ osteoclasts, ↑ collagen synthesis, ↑ gut Ca²⁺. Best for preventing rapid bone loss in early menopause, especially with vasomotor symptoms. Contraindicated: pregnancy, breast or estrogen-dependent cancer, undiagnosed bleeding, VTE/stroke/MI, migraine with aura.
9. Q30Estrogen side effects?

   Abnormal vaginal bleeding, vaginal candidiasis, breast tenderness, VTE, headache, melasma, ↑ BP, ↑ triglycerides.
10. Q31Raloxifene: benefits, risks and ideal patient?

    Reduces vertebral fractures 30–50% but NOT hip or non-vertebral; reduces ER+ breast cancer risk 50–75%; no uterine cancer risk. Risks: VTE (DVT/PE), hot flashes, leg cramps. Ideal: younger postmenopausal woman at vertebral fracture risk, especially with breast cancer risk, without VTE risk or major menopausal symptoms.
11. Q32Teriparatide/abaloparatide adverse effects and contraindications?

    Adverse: hypercalcemia, hypercalciuria/kidney stones, orthostatic hypotension, dizziness, nausea, headache. Avoid with ↑ osteosarcoma risk: Paget disease, children (open epiphyses), prior skeletal radiation, unexplained ↑ ALP, bone metastases or skeletal malignancy. Contraindicated: hypercalcemia, other metabolic bone disease.
12. Q33Romosozumab: key risk?

    Boxed warning: possible ↑ MI, stroke and cardiovascular death. Do not start within a year of MI or stroke. Also contraindicated with hypocalcemia.
13. Q34What is estrogen approved for in bone?

    Prevention (not treatment) of postmenopausal osteoporosis; it consistently raises spine and hip BMD, with a dose-dependent effect.
14. Q35What other side effect can oral bisphosphonates cause?

    Bone, joint or muscle pain (in addition to GI irritation).
15. Q36Does high cholesterol rule out raloxifene?

    No — raloxifene actually lowers LDL. Its key contraindication is a history of VTE.
16. Q37How well does denosumab work?

    It lowers vertebral fractures by ~68%, hip fractures by ~40% and non-vertebral fractures by ~20%, and raises BMD more than bisphosphonates.
17. Q38Who gets teriparatide or abaloparatide?

    They reduce vertebral and non-vertebral fractures and are approved for high-risk postmenopausal women, men with primary or hypogonadal osteoporosis, and glucocorticoid-induced osteoporosis. High risk = prior fragility fracture, multiple risk factors, or failure of/intolerance to other therapy.
18. Q39How does romosozumab compare?

    It raises BMD more than bisphosphonates and reduces vertebral, non-vertebral and hip fractures. Contraindications: MI/stroke in the past year, uncorrected hypocalcemia, systemic hypersensitivity.

Key questions

1. Q40What defines low risk and what do you do?

   No prior fracture, T-score > −1, low FRAX (<20% MOF, <3% hip) → non-pharmacologic management; may consider estrogen.
2. Q41What defines moderate risk?

   No prior fracture, T-score −1 to −2.5, low FRAX → some benefit from antiresorptive monotherapy: estrogen in early menopause, raloxifene (EAA) in 50s–60s, antiresorptives mid/late 60s.
3. Q42What defines high risk?

   Older single fracture (>2 years ago) or T-score ≤ −2.5, or T-score −1 to −2.5 with high FRAX → an antiresorptive is usually initial therapy (anabolics appropriate for some).
4. Q43What defines very high risk?

   Recent fracture (within 1–2 years), multiple fractures, T-score < −3.0, very high FRAX, or fractures on therapy/glucocorticoids/injurious falls → anabolic first, then a potent antiresorptive.
5. Q44What is the single most important risk factor for future fracture?

   A prior fracture — "fractures beget fractures"; risk is highest in the 1–2 years after a fracture (imminent risk).
6. Q45Which therapy for a woman in early menopause with hot flashes and bone loss?

   Estrogen — ideal to prevent rapid early-menopausal bone loss, especially with vasomotor symptoms; follow with a bisphosphonate when stopping.
7. Q46A recent vertebral fracture plus an MI 6 months ago?

   Very high risk → anabolic first, but avoid romosozumab (MI within a year) → use a PTH analog (teriparatide/abaloparatide), then an antiresorptive.
8. Q47An uninsured patient at high risk?

   An oral bisphosphonate (alendronate/risedronate) — first line, generic, accessible.
9. Q48Advanced CKD on dialysis with osteoporosis?

   Bisphosphonates contraindicated; denosumab is not renally cleared but causes severe hypocalcemia — only if calcium/mineral metabolism can be corrected and closely monitored.
10. Q49Which class has the strongest fracture-reduction evidence?

    Bisphosphonates — the most potent oral antiresorptives with the most robust fracture data.
11. Q50Postmenopausal, family history of osteoporosis, no fractures, T-score above −2.5 — options?

    Raloxifene or a bisphosphonate.
12. Q51Recent minimal-trauma fracture — estrogen or raloxifene?

    Skip both; start a bisphosphonate (or an anabolic if very high risk).

Key questions

1. Q52What must follow any anabolic course?

   An antiresorptive agent — to consolidate and enhance the gains; without it, the new bone is lost.
2. Q53Why give the anabolic first?

   An anabolic given AFTER antiresorptive therapy has less effect on BMD and fracture risk; given first, gains are larger.
3. Q54What happens if you switch from denosumab to a PTH analog?

   Delay or attenuation of effect or even bone loss, especially at cortical sites (hip).
4. Q55What happens when denosumab is stopped?

   Rebound RANKL activity → rapid rise in resorption, fall in BMD and ↑ risk of multiple vertebral fractures (as early as 7 months, average 19 months after the last dose).
5. Q56How do you stop denosumab safely?

   Do not give doses late, do not casually discontinue — NO drug holiday. If stopping, follow with a bisphosphonate to blunt the rebound.
6. Q57What is a drug holiday, and for which drugs?

   Only for bisphosphonates. After 3–5 years, reassess: if low/moderate risk, a temporary holiday; if still high risk, continue or change. It is a holiday, not retirement — treatment resumes.
7. Q58Why can bisphosphonates have a holiday?

   Long half-life and skeletal retention → benefits wane slowly after stopping; BMD gains plateau after ~4–5 years; atypical femoral fracture risk falls after stopping.
8. Q59Does any drug keep working after it is stopped?

   No — all drugs stop working when stopped; bisphosphonates just wear off slowest. Estrogen and denosumab lose benefit rapidly.
9. Q60What must follow estrogen when it is stopped?

   A bisphosphonate — stopping estrogen causes rapid BMD loss (mimics menopause).

Key questions

1. Q61Can osteoporosis be cured?

   No — it can be treated effectively and fracture risk reduced, but it is a lifelong disease like diabetes or hypertension.
2. Q62Should the diagnosis change to "osteopenia" once BMD improves?

   No. Retaining the diagnosis avoids a false sense of security, stopping needed medication, loss of insurance coverage and changes in allowed BMD testing frequency.
3. Q63How long does denosumab work?

   No time limit — BMD keeps rising for up to 10 years (no plateau, unlike bisphosphonates), with persistent fracture reduction.
4. Q64What happens to bisphosphonate benefit over time?

   BMD rises for ~4–5 years then plateaus; fracture protection begins within 12 months and persists; reassess at 3–5 years.
5. Q65What tailors the plan?

   Baseline fracture risk, fracture history, comorbidities (CKD, CV disease, VTE, cancer), age/menopause stage, patient preference and shared decision-making.
6. Q66What does the lecture tell patients in summary?

   All approved drugs raise BMD and reduce fractures; only anabolics build new bone; any treatment beats none; very high risk → start anabolic; anabolic must be followed by antiresorptive; holidays only for bisphosphonates; lifelong attention.