12.5 Hormone Therapy, Bisphosphonates, Antihistamines, Growth Factors & Complementary Agents
Key Takeaways
Oral bisphosphonates inhibit osteoclast farnesyl pyrophosphate synthase and must be taken fasting with a full glass of water while staying upright for 30 minutes; rare adverse effects are osteonecrosis of the jaw and atypical femoral fractures.
Denosumab is a RANKL antibody given every 6 months; stopping it without a follow-on agent causes rebound vertebral fractures, and it carries a boxed warning for severe hypocalcemia in advanced CKD.
Estrogen-containing hormone therapy and raloxifene increase venous thromboembolism risk, which compounds the risk from foot surgery and immobilization.
First-generation H1 antihistamines such as diphenhydramine are sedating and anticholinergic and are best avoided in older adults; second-generation agents such as cetirizine, loratadine and fexofenadine are minimally sedating.
Becaplermin (recombinant PDGF-BB) gel is FDA-approved for diabetic neuropathic foot ulcers with adequate blood supply; supplements are not FDA-approved for efficacy, and St. John's wort, ginkgo, fish oil and red yeast rice cause clinically important interactions.
12.5 Hormone Therapy, Bisphosphonates, Antihistamines, Growth Factors & Complementary Agents
The outline groups other pharmaceutical agents (hormone therapy, bisphosphonates, antihistamines and growth factors) and complementary and alternative agents (cannabinoids, vitamins, supplements and herbal products). Bone-active drugs matter for fracture and fusion healing, growth factors are used in diabetic wound care, and many patients take supplements without mentioning them.
Hormone Therapy
| Agent | Indications | Key risks and interactions |
|---|---|---|
| Estrogen with or without progestin (menopausal hormone therapy) | Vasomotor symptoms, prevention of genitourinary atrophy | Venous thromboembolism, stroke; with a progestin, breast cancer risk; unopposed estrogen raises endometrial cancer risk |
| Combined oral contraceptives | Contraception | VTE risk, which adds to the risk from lower extremity surgery, casting and immobilization; risk is higher in smokers older than 35 |
| Raloxifene (SERM) | Osteoporosis, breast cancer risk reduction | VTE, hot flashes, leg cramps |
| Tamoxifen (SERM) | Breast cancer | VTE, endometrial cancer |
| Levothyroxine | Hypothyroidism | Narrow therapeutic range; take on an empty stomach and separate from calcium, iron and PPIs; overtreatment causes atrial fibrillation and bone loss |
| Testosterone | Hypogonadism | Erythrocytosis, possible VTE, acne |
| Glucocorticoids | Anti-inflammatory and replacement | Covered in 11.3 and 12.4 |
Bone-Active Agents
| Drug | Mechanism | Key points |
|---|---|---|
| Oral bisphosphonates (alendronate, risedronate) | Bind hydroxyapatite; nitrogen-containing agents inhibit farnesyl pyrophosphate synthase in osteoclasts, causing loss of function and apoptosis | Take fasting with a full glass of plain water and remain upright for 30 minutes (pill esophagitis); avoid with severe CKD; rare osteonecrosis of the jaw and atypical femoral fractures; a drug holiday is considered after about 3–5 years in lower-risk patients |
| Zoledronic acid (IV) | Same class, given yearly | Acute-phase flu-like reaction; renal monitoring |
| Denosumab | Monoclonal antibody to RANKL, given every 6 months | Rebound multiple vertebral fractures if stopped without a follow-on agent; boxed warning for severe hypocalcemia in advanced CKD |
| Teriparatide, abaloparatide | PTH or PTHrP analogs given intermittently, which are anabolic | Hypercalcemia, orthostasis; given daily by injection |
| Romosozumab | Antibody to sclerostin, which increases bone formation and reduces resorption | Boxed warning for MI, stroke and cardiovascular death |
| Calcitonin | Inhibits osteoclasts | Weak antifracture effect; nasal formulation |
Podiatric relevance. Low bone density, vitamin D deficiency and anti-resorptive history are considered when planning arthrodesis or managing stress fractures. Charcot neuroarthropathy is managed with offloading and immobilization. Trials of bisphosphonates in active Charcot foot have not shown clinically meaningful benefit, and current diabetic foot guidance does not recommend them routinely.
Antihistamines
| Class | Examples | Features |
|---|---|---|
| First-generation H1 antagonists | Diphenhydramine, hydroxyzine, chlorpheniramine, promethazine | Cross the blood-brain barrier: sedation, anticholinergic effects (urinary retention, confusion); on lists of drugs to avoid in older adults |
| Second-generation H1 antagonists | Cetirizine, loratadine, fexofenadine | Minimal sedation; first choice for urticaria and allergic rhinitis |
| H2 antagonists | Famotidine | Acid suppression (12.3); sometimes added for urticaria and infusion reactions |
Antihistamines treat urticaria, pruritus and vancomycin infusion (flushing) reactions (11.1). They are adjuncts, not substitutes, for epinephrine in anaphylaxis.
Growth Factors
- Becaplermin gel (recombinant human PDGF-BB) is FDA-approved for lower extremity diabetic neuropathic ulcers that extend into subcutaneous tissue or deeper and have an adequate blood supply. It is used alongside debridement, offloading and infection control. Its earlier boxed warning about cancer mortality was removed from the label in 2018.
- Hematopoietic growth factors: filgrastim and pegfilgrastim (G-CSF) shorten chemotherapy-induced neutropenia and cause bone pain. Erythropoiesis-stimulating agents (epoetin alfa, darbepoetin) treat anemia of CKD and chemotherapy but carry boxed warnings for thrombosis, stroke and mortality when hemoglobin is pushed too high. Thrombopoietin receptor agonists (romiplostim, eltrombopag) treat immune thrombocytopenia.
- Routine G-CSF is not recommended for treating diabetic foot infection.
Complementary and Alternative Agents
Under the Dietary Supplement Health and Education Act (1994), supplements do not need FDA approval for efficacy before marketing. Product content and purity vary, so always ask about them during medication reconciliation.
| Agent | Proposed use | Clinically important risks |
|---|---|---|
| Cannabinoids: THC (CB1 agonist), CBD (non-intoxicating) | Pain, nausea, seizures | Sedation, cognitive and psychiatric effects; CBD inhibits CYP2C19 and CYP3A4 (raises clobazam and warfarin effect) and can raise liver enzymes. Prescription products include dronabinol and nabilone (chemotherapy nausea, appetite) and purified CBD for specific seizure disorders. Legal status differs between federal and state law |
| Vitamins in high doses | General health | Vitamin A: teratogenic and hepatotoxic. Vitamin B6: sensory neuropathy with chronic high intake. Vitamin D: hypercalcemia. Niacin: flushing and hepatotoxicity. Vitamin E: bleeding. Vitamin K: lowers warfarin effect |
| St. John's wort | Depression | CYP3A4 and P-glycoprotein induction; serotonin syndrome |
| Ginkgo, garlic, ginger, fish oil | Circulation, cardiovascular health | Antiplatelet effects with bleeding risk; many surgeons ask patients to stop them before surgery |
| Glucosamine and chondroitin | Osteoarthritis | Inconsistent benefit; possible INR increase with warfarin |
| Red yeast rice | Cholesterol | Contains monacolin K, chemically identical to lovastatin: myopathy and CYP3A4 interactions |
| Licorice (glycyrrhizin) | Digestive complaints | Pseudohyperaldosteronism: hypertension, hypokalemia, edema |
| Kava | Anxiety | Hepatotoxicity |
| Ephedra (ma huang) | Weight loss | FDA ban (2004) after strokes, MIs and arrhythmias |
Important
A supplement history is part of a complete medication history. Bleeding after surgery, an unstable INR, unexplained hypokalemia or statin-like myopathy can all trace back to products patients regard as "natural."
A patient beginning alendronate for osteoporosis asks how to take it. Which instruction is correct and explains why?
Take it with breakfast and milk to reduce stomach upset, because calcium improves absorption
Chew the tablet with orange juice, because acid activates the drug
Take it at bedtime lying down, so it stays in the esophagus longer for better absorption
Take it fasting with a full glass of plain water and stay upright for 30 minutes
A patient with a neuropathic plantar diabetic ulcer extending into subcutaneous tissue has palpable pedal pulses and no active infection after debridement. Which topical agent is FDA-approved for this indication?
Imiquimod cream
Silver sulfadiazine 1% cream
Mupirocin ointment
Becaplermin gel (PDGF-BB)
A patient taking simvastatin develops proximal myalgias and a raised creatine kinase after starting a supplement "to lower cholesterol naturally." Which supplement best explains this?
Red yeast rice
St. John's wort
Glucosamine sulfate
Ginkgo biloba
Sections you finish are checked off in the contents.