Category:Antiresorptives: Difference between revisions

An antiresorptive is a medicine that reduces bone resorption by osteoclasts, slowing the loss of bone matrix and so the development or progression of osteoporosis, the progression of skeletal metastatic disease, and the abnormal bone turnover of Paget's disease and selected metabolic bone disorders. The category includes the bisphosphonates (the largest single subclass, described in detail on its own page), the RANKL-pathway monoclonal antibody denosumab, the selective estrogen-receptor modulators with bone activity (raloxifene, bazedoxifene), the older calcitonin, and the sclerostin antibody romosozumab whose dual antiresorptive and anabolic action straddles the category boundary.

The pharmacological history of antiresorption is a four-decade story of progressively more selective inhibition of the osteoclast. Estrogen replacement (described under sex hormones and hormone replacement therapy) was the first effective antiresorptive medicine, with the suppression of bone loss in postmenopausal women established in observational and randomised data through the 1980s and 1990s. The 2002 Women's Health Initiative reframing of the risk-benefit balance of long-term combined oral hormone replacement substantially restricted the use of estrogen-only and combined hormone replacement for the osteoporosis indication; the medicines have since occupied a more selective place in postmenopausal women with significant menopausal symptoms in addition to bone-loss concern. The bisphosphonates from alendronate forward (1995; described under bisphosphonates) gave the first non-hormonal antiresorptive that was inexpensive, orally bioavailable in once-weekly dosing, and demonstrably effective in fracture prevention; they remain the foundation of the contemporary osteoporosis pharmacopoeia.

The RANKL pathway was identified in the late 1990s as the central signal for osteoclast differentiation and survival: osteoblasts and stromal cells produce the cytokine RANKL, which binds RANK on osteoclast precursors and signals their differentiation and activity. The fully human monoclonal antibody denosumab (Amgen, 2010 for osteoporosis as Prolia, 2010 for skeletal-related events in solid-tumour bone metastases and multiple myeloma as Xgeva) binds RANKL and prevents its receptor engagement, with effects comparable to those of bisphosphonates on bone-density gain and fracture reduction but a different safety profile, a different patient population (renal-impaired patients in whom bisphosphonate is contraindicated), and a markedly different consequence of treatment discontinuation. The 2017 recognition that abrupt denosumab discontinuation produces a rebound of bone resorption with multiple vertebral fractures within months has substantially reshaped the clinical use of the medicine; current practice is that denosumab not be discontinued without transition to a bisphosphonate to lock in the gains.

The selective estrogen receptor modulators are a mechanistically distinct antiresorptive class. Raloxifene (Evista, Eli Lilly 1997), an estrogen-receptor agonist in bone (where it suppresses osteoclast activation) and antagonist in breast (where it reduces breast cancer risk) and uterus (where it does not produce endometrial hyperplasia), reduces vertebral but not hip fracture in postmenopausal osteoporosis (MORE trial); it has the additional indication of breast cancer chemoprevention (STAR trial). The newer bazedoxifene combined with conjugated estrogens (Duavee, Pfizer 2013) provides estrogenic symptom relief and antiresorptive effect in postmenopausal women without progestin opposition (the bazedoxifene serves as a tissue-selective estrogen-receptor modulator that protects the endometrium).

The older calcitonin medicine (salmon calcitonin nasal spray as Miacalcin or Fortical) has minor antiresorptive effect and minor analgesic effect on the bone pain of recent vertebral fracture; the European Medicines Agency restricted its use in 2012 over a small but real signal of malignancy with chronic use, and it has retreated from routine osteoporosis practice. The sclerostin antibody romosozumab (Evenity, Amgen 2019), unique in the category in combining stimulation of bone formation with inhibition of bone resorption, is used for one year of treatment in postmenopausal women at high fracture risk followed by transition to a bisphosphonate or denosumab to maintain the gains; a small but real cardiovascular signal in the ARCH trial has restricted its use in patients with recent myocardial infarction or stroke.

The clinical management of osteoporosis with antiresorptive medicines follows a structured algorithm. Postmenopausal women and men over 50 at significant fracture risk (T-score below -2.5 by DEXA; fragility fracture history; FRAX-tool 10-year risk above country-specific threshold) are offered first-line oral bisphosphonate (alendronate or risedronate) or, in patients with intolerance or contraindication, intravenous zoledronate or subcutaneous denosumab. Patients at very high fracture risk (multiple vertebral fractures, T-score below -3.0 with prior fragility fracture, very low T-score in the context of corticosteroid use) are offered anabolic-first therapy (teriparatide or romosozumab) followed by sequential antiresorptive maintenance. The duration-of-treatment question (the "medicine holiday" decision after 3-5 years of oral bisphosphonate or 3 years of annual zoledronate, the no-holiday rule for denosumab) is one of the central clinical-decision points in contemporary osteoporosis care.

By mechanism:

• Bisphosphonates (cross-indexed; the largest antiresorptive subclass): alendronate, risedronate, ibandronate, zoledronate, pamidronate
• RANKL-pathway antagonist: denosumab (Prolia for osteoporosis; Xgeva for skeletal-related events in cancer)
• Selective estrogen receptor modulators (osteoporosis-active SERMs):
  • Raloxifene
  • Bazedoxifene (as monotherapy in Europe; combined with conjugated estrogens as Duavee in the U.S.)
  • Lasofoxifene
• Hormone replacement (cross-indexed under hormone replacement therapy and sex hormones):
  • Estradiol transdermal patch / oral / vaginal
  • Conjugated equine estrogens
  • Combined oral contraceptives in premenopausal antiresorptive use (selected indications)
• Calcitonin (largely retired):
  • Salmon calcitonin nasal spray (Miacalcin, Fortical)
  • Eel calcitonin (Europe)
• Sclerostin pathway (anabolic + antiresorptive):
  • Romosozumab (Evenity)
• Selective tartrate-resistant acid phosphatase inhibitors (in trial): odanacatib (withdrawn from development 2016 over cardiovascular signal)

The closely related anabolic medicines teriparatide (PTH 1-34) and abaloparatide (PTH-related peptide analogue) are not antiresorptive in mechanism but are listed under hormones and osteoporosis medications because they are part of the same clinical sequence.

The boundary of this category is "medicine whose principal mechanism is inhibition of bone resorption by osteoclasts." The anabolic medicines for osteoporosis (teriparatide, abaloparatide, the partly-anabolic romosozumab) are cross-listed where their dual mechanism justifies inclusion. The mineral supplements (calcium, vitamin D) are foundational supportive therapy for any osteoporosis regimen but are not antiresorptive in mechanism and are listed under their own categories. The medicines used in hypercalcemia of malignancy (intravenous bisphosphonate, denosumab, gallium nitrate, mithramycin in historical use) are antiresorptives by mechanism and are cross-listed here for that indication. The bone-targeted radiopharmaceuticals (samarium-153 EDTMP for bone-metastasis pain, strontium-89, radium-223 for bone-metastatic prostate cancer) are not antiresorptives and are listed under antineoplastics.

This category page is an encyclopedia article about its subject. The actual index of medicines belonging to the category is generated automatically by the wiki engine, from category-membership declarations on the individual medicine pages, and appears at the foot of the page below the references.