Bisphosphonates are a class of medications that slow bone loss by reducing the activity of osteoclasts, the cells that break down bone. They are the most widely prescribed treatment for osteoporosis and have been in clinical use since the 1990s.

The 2023 American College of Physicians (ACP) guidelines recommend bisphosphonates as first-line treatment for most people with osteoporosis. The four bisphosphonates currently used for osteoporosis are alendronate (Fosamax), risedronate (Actonel), ibandronate (Boniva), and zoledronic acid (Reclast).

Bisphosphonates bind to the surface of bone and are absorbed by osteoclasts (bone-removing cells) during normal bone remodeling. Once inside the osteoclast, the bisphosphonate disrupts its function and accelerates cell death. This slows the rate of bone breakdown while allowing osteoblasts (bone-building cells) to continue working.

The net result is that bone density is maintained or increased and fracture risk is reduced. Bisphosphonates also accumulate in bone tissue, which is why they continue to provide some protection even after you stop taking them — the basis for the drug holiday approach.

Prolia (denosumab) is a monoclonal antibody that works by blocking RANKL, a protein required for the formation and survival of osteoclasts. While both Prolia and bisphosphonates are antiresorptive medications (they slow bone breakdown), they have different mechanisms.

A key difference: bisphosphonates accumulate in bone and have a residual effect after stopping, while Prolia's effects reverse rapidly when discontinued — which is why Prolia should never be stopped without transitioning to another medication.

EVENITY (romosozumab) is a monoclonal antibody that blocks sclerostin, a protein that inhibits bone formation. It is classified as an anabolic (bone-building) agent with additional antiresorptive properties — meaning it both builds new bone and slows bone breakdown.

EVENITY is given as a 12-month course of monthly injections and must be followed by a bisphosphonate or other antiresorptive medication to preserve the bone gains.

Reclast is the brand name for zoledronic acid, an intravenous bisphosphonate given as a once-yearly infusion for osteoporosis. It reduces the risk of vertebral, non-vertebral, and hip fractures and avoids the gastrointestinal side effects of oral bisphosphonates.

Reclast is increasingly used as the preferred follow-on after EVENITY, with studies showing it retains 73–87% of bone density gains at the spine and hip.

Alendronate (brand name Fosamax) is the most widely prescribed bisphosphonate. It is taken as a weekly oral tablet and reduces the risk of vertebral, non-vertebral, and hip fractures. It has the most extensive long-term safety data of any bisphosphonate and is the most common follow-on after anabolic treatment in clinical trials.

Tymlos (abaloparatide) is a synthetic analogue of parathyroid hormone-related protein (PTHrP) and is classified as an anabolic (bone-building) agent. It is administered as a daily self-injection for up to 18 months and should be followed by a bisphosphonate or other antiresorptive medication to maintain the bone it has built.

Forteo (teriparatide) is a recombinant form of human parathyroid hormone (PTH) and is classified as an anabolic (bone-building) agent. It is administered as a daily self-injection for up to 24 months. Like other anabolic medications, Forteo should be followed by a bisphosphonate or other antiresorptive to preserve bone density gains.

Fosamax is the brand name for alendronate, the most widely prescribed oral bisphosphonate. It is taken as a weekly tablet on an empty stomach with a full glass of plain water. You must remain upright for at least 30 minutes after taking it without eating or drinking anything else.

Boniva is the brand name for ibandronate, available as a monthly oral tablet or quarterly IV infusion. It has strong evidence for reducing vertebral fractures, but the evidence for non-vertebral and hip fracture reduction is less robust than for alendronate, risedronate, or zoledronic acid.

Raloxifene (brand name Evista) mimics some of the protective effects of estrogen on bone. It reduces the risk of vertebral fractures in postmenopausal women but has not been shown to reduce hip fractures. It is generally considered a second-line option for osteoporosis treatment.

Zometa is the brand name for zoledronic acid used at higher doses in cancer treatment — for bone metastases, hypercalcemia of malignancy, and skeletal complications. The same active ingredient is used at a lower dose under the brand name Reclast for osteoporosis. The risk of side effects such as osteonecrosis of the jaw is substantially higher with cancer-dose Zometa (1–8%) than with osteoporosis-dose Reclast (0.01–0.06%).

Evista is the brand name for raloxifene. It works by mimicking estrogen's protective effects on bone without some of estrogen's risks to breast tissue. Evista reduces vertebral fracture risk in postmenopausal women but does not reduce hip fracture risk and is considered a second-line option.

Xgeva (denosumab) is a monoclonal antibody that blocks RANKL — the same mechanism as Prolia but at a higher dose (120 mg monthly vs. 60 mg every six months). Xgeva is used for cancer-related bone conditions such as bone metastases and giant cell tumors. Despite sharing the same active ingredient as Prolia, they are prescribed for different conditions at very different doses.

Zoledronic acid is the most potent bisphosphonate available. For osteoporosis it is marketed as Reclast (once-yearly IV infusion). For cancer-related bone complications it is marketed as Zometa (higher doses, more frequent). Reclast reduces vertebral, non-vertebral, and hip fractures, avoids GI side effects of oral bisphosphonates, and is increasingly preferred as the follow-on therapy after EVENITY.

This is a topic of active debate. The American Association of Oral and Maxillofacial Surgeons (AAOMS) previously recommended a 2-month drug holiday before invasive dental procedures for patients on bisphosphonates for more than 4 years. However, their 2022 position paper update noted this recommendation is controversial, as multiple studies have found no clear benefit to stopping bisphosphonates before dental extractions in osteoporosis patients.

A 2025 study in Nature Communications found that for patients on intravenous bisphosphonates, the risk of jawbone osteonecrosis was substantially lower when treatment was paused for more than 90 days, and lowest when paused for more than one year.

Importantly, the overall risk of osteonecrosis of the jaw in osteoporosis patients on standard bisphosphonate doses is very low (0.01–0.06%).

Do not stop your bisphosphonate without consulting both your prescribing physician and your dentist or oral surgeon. They can assess your specific risk factors — including how long you've been on the medication, which bisphosphonate you take, and your fracture risk — to determine the safest approach.