Osteoporosis Beyond Bisphosphonates: When Anabolic Drugs Like Romosozumab and Teriparatide Are Needed and What a Drug Holiday Means

Research-informed explainer — last updated April 12, 2026

Bisphosphonates remain effective for most patients with osteoporosis, but for those with very low bone density, recent fractures, or long-term bisphosphonate use, anabolic agents that actually build new bone — not just slow its loss — produce significantly better fracture outcomes. Knowing when to escalate, when to take a drug holiday, and why the sequence of therapy matters can protect bones over a lifetime.

This article draws on research by Neil Binkley, MD, Director of the UW Osteoporosis Clinical Research Program at the University of Wisconsin Hospitals and Clinics, who co-authored the FRAME trial of romosozumab in postmenopausal women (1,659 citations) and the AACE osteoporosis guidelines (1,144 and 1,058 citations); Sundeep Khosla, MD, at Mayo Clinic, whose comprehensive review of osteoporosis treatment developments and challenges (1,002 citations), OPG/RANKL/RANK minireview (1,404 citations), and ASBMR task force on bisphosphonate osteonecrosis of the jaw (1,642 citations) frame the biological rationale for sequencing; Matthew Drake, MD, Associate Professor of Medicine at Hospital for Special Surgery, who authored the definitive review of bisphosphonate mechanism and clinical practice (1,576 citations), the ASBMR task force report on long-term bisphosphonate management (649 citations), and the adverse effects implications paper (398 citations); Meryl LeBoff, MD, at Brigham and Women's Hospital and Harvard Medical School, co-author of the clinician's guide to osteoporosis (4,038 citations); and John Bilezikian, MD, at NewYork-Presbyterian/Columbia University, who published the original NEJM trial comparing PTH and alendronate alone or in combination (1,164 citations) — establishing the principle that concurrent bisphosphonate use can blunt anabolic effects.

What bisphosphonates do and when they are not enough

Bisphosphonates — alendronate, risedronate, zoledronic acid — work by inhibiting osteoclasts, the cells that break down bone. They do not build new bone; they slow the rate of loss. For most postmenopausal women with T-scores in the osteoporotic range (−2.5 or below), this is sufficient to reduce fracture risk meaningfully.

However, bisphosphonates accumulate in bone mineral over years and eventually saturate. The ASBMR drug holiday report (649 citations) defines when this becomes relevant: after 3–5 years of oral bisphosphonate or 3 years of intravenous zoledronic acid, a holiday of 2–3 years is appropriate for patients at moderate risk. During a holiday, the stored drug continues to protect bone for some time. But if fracture risk is high — very low T-score, multiple prior fractures, ongoing glucocorticoid use, age above 75 — a holiday is not safe, and escalation to anabolic therapy should be considered instead.

Teriparatide: the original anabolic

Teriparatide is a fragment of human PTH given as a daily subcutaneous injection. Rather than simply slowing bone loss, it stimulates osteoblasts — the cells that build bone — producing genuine increases in bone mineral density. In a landmark NEJM trial (1,164 citations), Dr. Bilezikian's group showed that concurrent alendronate blocked the anabolic effect of PTH: bone density at the hip and spine increased more with teriparatide alone than with the combination. This finding established the now-standard principle: start teriparatide alone, then follow with an antiresorptive to consolidate the gains. Teriparatide is given for a maximum of 24 months (or 18 months for abaloparatide, its newer analogue).

Romosozumab: building and blocking at once

Romosozumab is a monoclonal antibody that inhibits sclerostin — a protein that normally suppresses bone formation. By blocking sclerostin, romosozumab simultaneously increases bone formation and decreases bone resorption, a dual mechanism no previous drug achieved. The FRAME trial (1,659 citations), to which Dr. Binkley contributed, randomized 7,180 postmenopausal women to romosozumab 210 mg monthly versus placebo for 12 months, then transitioned all patients to denosumab. At 12 months, romosozumab reduced new vertebral fracture risk by 73% relative to placebo; after the denosumab transition at 24 months, the benefit was maintained. Clinical fractures were reduced by 36% at one year — a speed of benefit not seen with other agents.

One caveat: a head-to-head trial of romosozumab versus alendronate found a small excess of cardiovascular events in the romosozumab group. Romosozumab is not recommended within one year of a myocardial infarction or stroke.

The drug sequencing principle

The Lancet Diabetes & Endocrinology review (1,002 citations) by Dr. Khosla articulates the treatment sequencing logic:

• High-risk patients (multiple fractures, very low T-score): start with an anabolic (teriparatide or romosozumab), then follow with an antiresorptive
• Moderate-risk patients: bisphosphonate is appropriate first-line, with transition to anabolic if fractures occur on treatment or density remains very low
• After anabolic therapy: an antiresorptive (bisphosphonate or denosumab) is essential to preserve density gains; without it, bone density falls back toward baseline within months

Denosumab, a RANKL inhibitor that suppresses osteoclast formation, is a potent antiresorptive alternative to bisphosphonates with greater hip density gains — but it requires strict adherence; missing doses can cause rebound bone loss and increased fracture risk.

Drug holidays: who needs one and when

The ASBMR task force on long-term bisphosphonate use (649 citations) and the adverse effects paper (398 citations) define the rare but real risks that motivate drug holidays:

• Atypical femur fractures (AFF): transverse fractures of the femoral shaft associated with years of bisphosphonate use; risk approximately 1 in 1,000 after 3 years, rising to 1 in 100 after 8–10 years of high-dose use
• Osteonecrosis of the jaw (ONJ): extremely rare in osteoporosis treatment (estimated 1 in 10,000–100,000), much more common with high-dose IV bisphosphonates for cancer

A drug holiday reduces atypical fracture risk. It is appropriate for patients who have been on oral bisphosphonate for 5 years (or IV for 3 years) with a T-score above −2.5, no recent fractures, and low clinical risk score. Those with T-scores below −2.5, recent fracture, or ongoing risk factors should continue therapy rather than holiday — and may be candidates for anabolic escalation.

Questions to ask your doctor

• Have I been on a bisphosphonate long enough that a drug holiday should be considered, and is my fracture risk low enough to make that safe?
• Do my bone density results, fracture history, or risk factors qualify me for teriparatide or romosozumab?
• If I take an anabolic agent, what antiresorptive will follow it to preserve the bone I have built?
• Do I have any history of heart attack or stroke that would make romosozumab inadvisable?
• What is my FRAX score, and does it change the urgency of treatment escalation?
• How often should I have bone density testing while on my current medication?

The bottom line

Bisphosphonates are a sound first-line treatment for osteoporosis, but they are not the end of the conversation. Patients with very high fracture risk — severe bone loss, recent fractures, or fractures occurring on treatment — benefit substantially from anabolic therapy that builds bone rather than just slowing its loss. Drug holidays are appropriate for some long-term bisphosphonate users at moderate risk, but patients at high risk should stay on effective therapy rather than take a break.