Pharmacology of Drugs Affecting Calcium Balance (Bisphosphonates, PTH)

Introduction/Overview

The regulation of systemic calcium homeostasis is a critical physiological process, essential for neuromuscular function, cellular signaling, and skeletal integrity. Pharmacological intervention in calcium balance is primarily directed toward the management of metabolic bone diseases, most notably osteoporosis, Paget’s disease of bone, and disorders of calcium metabolism such as hypercalcemia of malignancy and hypoparathyroidism. Two principal classes of agents dominate this therapeutic landscape: bisphosphonates and parathyroid hormone (PTH) analogs. These drugs exert profound but opposing effects on bone remodeling, the continuous cycle of bone resorption by osteoclasts and bone formation by osteoblasts. An understanding of their pharmacology is fundamental for the rational treatment of bone disorders, which represent a significant and growing public health burden associated with aging populations.

The clinical relevance of these agents is substantial. Osteoporosis alone affects millions worldwide and is characterized by reduced bone mass and microarchitectural deterioration, leading to increased fracture risk. Pharmacotherapy aims to reduce this risk by modulating bone turnover. Bisphosphonates, as potent inhibitors of bone resorption, have been the cornerstone of anti-osteoporotic treatment for decades. In contrast, teriparatide, a recombinant fragment of PTH, represents the first widely available anabolic agent that stimulates new bone formation. The strategic use of these drugs, including sequential therapy, requires a detailed knowledge of their mechanisms, kinetics, and long-term effects.

Learning Objectives

• Describe the molecular and cellular mechanisms of action of bisphosphonates and parathyroid hormone analogs on bone remodeling.
• Compare and contrast the pharmacokinetic profiles of oral and intravenous bisphosphonates, including their unique absorption, distribution, and elimination characteristics.
• Identify the approved clinical indications for bisphosphonates and PTH analogs, and explain the rationale for their use in specific bone disorders.
• Analyze the major adverse effect profiles of these drug classes, including osteonecrosis of the jaw and atypical femoral fractures associated with long-term bisphosphonate use.
• Evaluate special considerations for the use of these agents in patients with renal impairment, during pregnancy, and in pediatric or geriatric populations.

Classification

Drugs affecting calcium balance for the treatment of bone diseases are classified primarily by their fundamental action on bone remodeling: as anti-resorptive agents or anabolic agents. This functional classification correlates with distinct chemical structures and origins.

Anti-resorptive Agents: Bisphosphonates

Bisphosphonates are synthetic analogs of inorganic pyrophosphate (PPi), characterized by a central phosphorus-carbon-phosphorus (P-C-P) backbone. This structure confers high affinity for bone mineral. They are further subclassified based on the presence or absence of a nitrogen atom in their R₂ side chain, which significantly influences their potency and mechanism.

• Non-Nitrogen-Containing Bisphosphonates (First Generation): These lack a nitrogen moiety in their side chain. Examples include etidronate and clodronate. Their mechanism involves the intracellular formation of cytotoxic, non-hydrolyzable analogs of adenosine triphosphate (ATP).
• Nitrogen-Containing Bisphosphonates (Second and Third Generation): These possess a nitrogen atom within various structures (alkyl chains, heterocyclic rings) on the R₂ side chain. This group is more potent and includes:
  • Alendronate, Risedronate, Ibandronate: Often termed second-generation, with simpler alkyl-amino side chains.
  • Zoledronate (Zoledronic Acid), Pamidronate: Considered more potent, third-generation agents. Zoledronate contains an imidazole ring, and pamidronate has an amino-alkyl chain.

Anabolic Agents: Parathyroid Hormone Analogs

This class consists of recombinant or synthetic fragments of endogenous parathyroid hormone. Their action is primarily anabolic, stimulating bone formation.

• Teriparatide: A recombinant human PTH fragment comprising the first 34 amino acids (rhPTH(1-34)). This fragment contains the bioactive region necessary for receptor activation.
• Abaloparatide: A synthetic analog of parathyroid hormone-related protein (PTHrP), consisting of its first 34 amino acids with specific modifications to enhance receptor selectivity and stability.
• Recombinant Full-Length Human PTH (rhPTH(1-84)): Used in some regions for the treatment of hypoparathyroidism, though its use in osteoporosis is less common than teriparatide.

Mechanism of Action

The mechanisms of action of bisphosphonates and PTH analogs are fundamentally distinct, targeting different phases and cell types within the bone remodeling unit.

Bisphosphonates: Inhibition of Osteoclastic Bone Resorption

The pharmacodynamic action of bisphosphonates is highly selective for bone, specifically targeting sites of active resorption. The process involves several sequential steps.

1. Bone Mineral Binding: The high affinity of the P-C-P backbone for hydroxyapatite crystals in bone mineral directs bisphosphonates preferentially to bone surfaces, particularly areas undergoing active remodeling where mineral exposure is high. This binding is rapid and concentration-dependent.

2. Osteoclast Uptake: During bone resorption, osteoclasts create an acidic microenvironment beneath their ruffled border, which solubilizes the mineral and releases the bound bisphosphonate. The drug is then internalized by the osteoclast via fluid-phase endocytosis.

3. Intracellular Mechanism: The mechanism diverges based on the chemical class.

• Non-Nitrogen-Containing Bisphosphonates (e.g., Clodronate, Etidronate): These are metabolically incorporated into non-hydrolyzable analogs of adenosine triphosphate (AppCp-type compounds). These cytotoxic metabolites accumulate within the osteoclast, inducing apoptosis (programmed cell death) and inhibiting resorptive function.
• Nitrogen-Containing Bisphosphonates (N-BPs; e.g., Alendronate, Risedronate, Zoledronate): These are not metabolized to ATP analogs. They potently inhibit the enzyme farnesyl pyrophosphate synthase (FPPS) in the mevalonate pathway. FPPS inhibition prevents the synthesis of isoprenoid lipids (farnesyl pyrophosphate and geranylgeranyl pyrophosphate) that are essential for the post-translational prenylation of small GTPase signaling proteins (e.g., Ras, Rho, Rac). Proper membrane localization and function of these GTPases are critical for osteoclast cytoskeletal organization, ruffled border formation, vesicular trafficking, and cell survival. Inhibition of prenylation disrupts these processes, leading to osteoclast apoptosis and a profound suppression of bone resorption. The potency of an N-BP correlates with its affinity for FPPS, with zoledronate being among the most potent.

4. Net Effect on Bone Remodeling: By reducing osteoclast number and activity, bisphosphonates decrease the depth and frequency of resorption pits. This leads to a reduction in bone turnover. The temporary imbalance between resorption and formation (the “remodeling transient”) results in a net gain in bone mineral density (BMD), as bone formation continues at existing remodeling sites while new resorption sites are suppressed. Over the long term, a new, lower steady-state of bone turnover is established, reducing the structural perforations that lead to fragility.

Parathyroid Hormone Analogs: Stimulation of Bone Formation

The action of endogenous PTH on bone is complex and biphasic, dependent on the pattern of exposure. Continuous elevation of PTH, as seen in hyperparathyroidism, promotes net bone resorption. In contrast, intermittent, daily subcutaneous administration of PTH analogs produces a net anabolic effect. The primary molecular target is the PTH/PTHrP type 1 receptor (PTH1R), a G protein-coupled receptor expressed on osteoblasts and osteocytes.

1. Receptor Activation and Signaling: Binding of teriparatide or abaloparatide to PTH1R activates multiple signaling pathways, primarily G_s-mediated cAMP/protein kinase A (PKA) and G_q-mediated phospholipase C/protein kinase C (PKC) pathways. These signals have several downstream effects on osteoblast lineage cells.

2. Cellular and Tissue-Level Effects:

• Stimulation of Osteoblast Differentiation and Activity: PTH signaling promotes the differentiation of pre-osteoblasts into mature, bone-forming osteoblasts and directly increases the synthetic activity of existing osteoblasts. This leads to increased production of bone matrix (osteoid).
• Inhibition of Osteoblast Apoptosis: PTH analogs reduce the programmed cell death of osteoblasts, thereby prolonging their bone-forming lifespan.
• Activation of Bone Lining Cells: PTH can convert quiescent bone lining cells into active osteoblasts, rapidly initiating bone formation on quiescent surfaces.
• Modulation of Osteoclast Activity (Indirect): The anabolic effect is not purely osteoblast-centric. PTH increases the expression of receptor activator of nuclear factor kappa-B ligand (RANKL) and decreases osteoprotegerin (OPG) production by osteoblasts and osteocytes. This RANKL/OPG ratio increase stimulates osteoclast differentiation and activity. This controlled, coupled increase in resorption is thought to be necessary for the anabolic response, possibly by clearing old bone to make space for new bone formation and by releasing bone-derived growth factors like insulin-like growth factor-1 (IGF-1).

3. Net Effect on Bone Remodeling: With intermittent dosing, the anabolic effects on osteoblasts outweigh the catabolic effects mediated via osteoclasts. This results in a net increase in bone formation, manifested as improved trabecular connectivity, increased cortical thickness, and overall enhancement of bone mass and strength. Abaloparatide is designed to have greater selectivity for the RG conformation of the PTH1R, which is associated with more transient signaling and a potentially more pronounced anabolic profile compared to teriparatide.

Pharmacokinetics

The pharmacokinetic properties of bisphosphonates and PTH analogs are markedly different, profoundly influencing their routes of administration, dosing schedules, and clinical utility.

Bisphosphonates

The pharmacokinetics of bisphosphonates are characterized by very low oral bioavailability, extensive and rapid uptake into bone, and prolonged elimination.

Absorption: Oral bioavailability is generally poor, typically less than 1% for alendronate and risedronate, and approximately 0.6% for ibandronate. Absorption occurs primarily in the upper small intestine via paracellular transport. The presence of food, beverages (especially coffee and orange juice), and divalent cations (Ca²⁺, Mg²⁺, Fe²⁺) can chelate the drug, reducing absorption by over 90%. Therefore, strict dosing instructions mandate administration with plain water after an overnight fast, remaining upright, and postponing food for at least 30-60 minutes.

Distribution: Distribution is multiphasic. Following intravenous administration or absorption, there is a rapid distribution phase from plasma to bone and a very slow terminal elimination phase. The volume of distribution is relatively low, approximating extracellular fluid volume for the fraction not bound to bone. Approximately 20-80% of the administered dose is taken up by bone, with the affinity for hydroxyapatite being a key determinant. The fraction bound to bone is proportional to the dose and the rate of bone turnover. The remainder is excreted unchanged in the urine.

Metabolism: Bisphosphonates are not metabolized systemically. Non-nitrogen-containing bisphosphonates may be intracellularly metabolized to cytotoxic ATP analogs within osteoclasts, as described. Nitrogen-containing bisphosphonates are not metabolized and act as direct enzyme inhibitors.

Excretion: Renal excretion of the unbound fraction is the primary route of elimination from the systemic circulation. The clearance is directly proportional to renal function (glomerular filtration rate, GFR). The half-life in plasma is short, typically 30 minutes to 2 hours. However, the effective half-life, governed by the slow release from bone mineral reservoirs, is extremely long, ranging from several months to over 10 years, depending on the specific drug and skeletal site. This prolonged skeletal retention underpins both the extended duration of therapeutic effect and the potential for very long-term adverse effects.

Dosing Considerations: The long skeletal half-life permits infrequent dosing regimens. Oral bisphosphonates are typically administered daily, weekly, or monthly. Intravenous formulations (pamidronate, ibandronate, zoledronate) can be given every 3 months (ibandronate) or even once yearly (zoledronate for osteoporosis).

Parathyroid Hormone Analogs (Teriparatide, Abaloparatide)

As peptides, these agents have pharmacokinetic profiles unsuitable for oral administration.

Absorption: They are administered via daily subcutaneous injection. Absorption from the injection site is rapid, with bioavailability approaching 95%.

Distribution: The volume of distribution is limited, roughly equivalent to extracellular fluid volume (≈ 0.12 L/kg for teriparatide). They do not accumulate in bone like bisphosphonates.

Metabolism: Metabolism occurs primarily via non-specific enzymatic degradation (e.g., by hepatic and renal peptidases) and by the reticuloendothelial system. The metabolic pathways are not dependent on cytochrome P450 enzymes.

Excretion: The clearance of teriparatide is high (≈ 62 L/hr in women), exceeding hepatic blood flow, suggesting extra-hepatic clearance. Renal clearance also contributes. The terminal half-life (t_1/2) in plasma is short, approximately 1 hour for teriparatide when administered subcutaneously, and about 1.7 hours for abaloparatide. This rapid clearance is essential for the intermittent, pulsatile action required for an anabolic effect.

Dosing Considerations: The short half-life necessitates daily subcutaneous administration. The recommended treatment course is limited to 18-24 months for teriparatide due to a black box warning regarding osteosarcoma observed in rat studies with lifelong, high-dose exposure.

Therapeutic Uses/Clinical Applications

The clinical applications of these agents are centered on disorders of bone metabolism and calcium homeostasis, with osteoporosis being the most prevalent indication.

Bisphosphonates

• Osteoporosis (Postmenopausal, Male, and Glucocorticoid-Induced): This is the primary indication. Bisphosphonates (alendronate, risedronate, ibandronate, zoledronate) are first-line anti-resorptive agents proven to reduce the risk of vertebral, non-vertebral, and hip fractures. The choice between oral and intravenous routes depends on patient preference, gastrointestinal tolerance, adherence, and renal function.
• Paget’s Disease of Bone: This condition of focal, chaotic bone remodeling responds well to potent bisphosphonates, particularly intravenous zoledronate (often as a single infusion) or oral risedronate. Treatment aims to suppress disease activity, alleviate bone pain, and prevent complications like deformity, fracture, and neurological compression.
• Hypercalcemia of Malignancy: Potent intravenous bisphosphonates (pamidronate, zoledronate) are effective first-line treatments. They inhibit osteoclast-mediated bone resorption, which is often the primary driver of hypercalcemia in cancer patients. Zoledronate is generally more potent and has a longer duration of action than pamidronate.
• Prevention and Treatment of Skeletal-Related Events (SREs) in Metastatic Bone Disease: In patients with bone metastases from solid tumors (e.g., breast, prostate, lung) or multiple myeloma, intravenous bisphosphonates (zoledronate, pamidronate) and the RANKL inhibitor denosumab reduce the incidence of SREs, defined as pathological fracture, spinal cord compression, need for radiation or surgery to bone, and hypercalcemia.
• Off-label Uses: These may include the treatment of osteogenesis imperfecta in children and adults, and the management of certain forms of fibrous dysplasia.

Parathyroid Hormone Analogs

• Osteoporosis at High Risk for Fracture: Teriparatide and abaloparatide are indicated for the treatment of postmenopausal women and men with osteoporosis who are at high risk for fracture. This includes patients with severe osteoporosis (very low BMD, multiple fractures), those who have failed or are intolerant to other therapies, or those with glucocorticoid-induced osteoporosis. They are particularly considered for patients where an anabolic (bone-building) effect is desired, such as those with very low trabecular bone score or multiple vertebral fractures.
• Hypoparathyroidism: Recombinant human PTH(1-84) (not teriparatide) is approved in some regions for the management of hypoparathyroidism that cannot be adequately controlled with calcium and active vitamin D analogs. It reduces the need for high-dose calcium and vitamin D supplementation and may improve quality of life.
• Considerations for Sequential Therapy: Due to the “anabolic window” concept, it is common clinical practice to follow a course of anabolic therapy (e.g., 18-24 months of teriparatide) with an anti-resorptive agent (usually a bisphosphonate or denosumab) to consolidate and maintain the gained bone mass.

Adverse Effects

The adverse effect profiles are distinct and often related to the drugs’ mechanisms and pharmacokinetics.

Bisphosphonates

Common Side Effects:

• Gastrointestinal: Oral bisphosphonates are associated with esophageal irritation, dyspepsia, abdominal pain, nausea, and diarrhea. These effects are often mitigated by proper administration technique (upright posture, adequate water).
• Acute-Phase Reaction: Following the first intravenous dose of an N-BP (especially zoledronate), a transient, flu-like syndrome may occur in 10-40% of patients. Symptoms include fever, myalgia, arthralgia, headache, and malaise, typically peaking within 24-48 hours and resolving within 3 days. It is mediated by the release of pro-inflammatory cytokines and is less common with subsequent doses. Pre-treatment with acetaminophen can be preventive.
• Hypocalcemia: A predictable pharmacodynamic effect due to inhibition of bone resorption. It is usually mild and asymptomatic but can be significant in patients with vitamin D deficiency or impaired parathyroid hormone response. Ensuring adequate calcium and vitamin D intake is mandatory.

Serious/Rare Adverse Reactions:

• Osteonecrosis of the Jaw (ONJ): This is a rare but serious condition characterized by exposed, necrotic bone in the maxillofacial region that persists for more than 8 weeks in a patient with no history of radiation to the jaw. Risk is highest with high-dose, frequent intravenous N-BPs in oncology patients (≈1-15%). Risk in the osteoporosis population is very low (≈0.001-0.01% per year). Major risk factors include invasive dental procedures (e.g., tooth extraction), poor oral hygiene, and prolonged duration of therapy. Preventive dental care is crucial.
• Atypical Femoral Fractures (AFFs): These are low-energy, transverse or short oblique fractures in the subtrochanteric region or femoral shaft. They may be preceded by prodromal thigh pain and often present with a characteristic cortical “beaking” on radiographs. The absolute risk is low but increases with longer duration of therapy (e.g., >3-5 years). The pathogenesis is not fully understood but may involve oversuppression of bone turnover, leading to impaired microdamage repair and altered material properties of bone.
• Severe Bone, Joint, or Muscle Pain: Occasionally severe and incapacitating musculoskeletal pain can occur, which may begin days to months after initiation. Symptoms usually resolve upon discontinuation.
• Ocular Inflammation: Rare cases of uveitis, scleritis, and episcleritis have been reported.
• Renal Toxicity: Intravenous bisphosphonates, particularly when infused too rapidly or in patients with pre-existing renal impairment, can cause deterioration in renal function, including acute renal failure. Proper hydration and dose adjustment for renal function are essential.

Black Box Warnings: For intravenous bisphosphonates used in cancer patients, there are warnings for renal impairment and ONJ.

Parathyroid Hormone Analogs

Common Side Effects:

• Hypercalcemia: Mild, transient hypercalcemia, typically occurring 4-6 hours after injection, is common but usually asymptomatic. Monitoring of serum calcium is recommended.
• Orthostatic Hypotension: Teriparatide can cause a transient decrease in blood pressure, sometimes with dizziness, within the first several hours after injection. The first dose should be administered in a setting where the patient can sit or lie down if needed.
• Injection Site Reactions: Mild, transient erythema, pain, or bruising may occur.
• Nausea, Leg Cramps, Headache: These are reported with low frequency.

Serious/Rare Adverse Reactions:

• Osteosarcoma: A black box warning exists for teriparatide and abaloparatide based on the development of osteosarcoma in rats given lifelong, high-dose exposure. No definitive causal link has been established in humans, but the treatment course is limited to 2 years, and these drugs are contraindicated in patients at increased baseline risk for osteosarcoma (e.g., Paget’s disease of bone, prior skeletal radiation, open epiphyses).
• Hyperuricemia and Gout: Teriparatide can increase serum uric acid levels, potentially precipitating gout in susceptible individuals.
• Increased Urinary Calcium Excretion: This may predispose to nephrolithiasis, although the overall risk appears low. A history of active urolithiasis is a relative contraindication.

Drug Interactions

Bisphosphonates

• Calcium, Magnesium, Iron, and Aluminum Supplements/Antacids: These divalent and trivalent cations form insoluble complexes with oral bisphosphonates in the GI tract, drastically reducing absorption. Administration must be separated by at least 30-60 minutes, preferably longer.
• Other Oral Medications: Any substance that interferes with gastric emptying or mucosal integrity may potentially alter absorption. It is generally advised to take oral bisphosphonates alone, with water, and to delay other medications.
• Aminoglycosides: Concurrent use with intravenous bisphosphonates may have an additive hypocalcemic effect.
• Non-Steroidal Anti-Inflammatory Drugs (NSAIDs): May increase the risk of GI irritation when used with oral bisphosphonates.
• Nephrotoxic Drugs (e.g., Aminoglycosides, Cisplatin, Loop Diuretics): May increase the risk of renal impairment when used with intravenous bisphosphonates.
• Contraindications: Hypocalcemia; severe renal impairment (CrCl < 30-35 mL/min for most oral agents; specific thresholds exist for IV formulations, e.g., zoledronate is contraindicated if CrCl < 35 mL/min in some indications); esophageal abnormalities that delay emptying (achalasia, stricture) for oral bisphosphonates; and known hypersensitivity.

Parathyroid Hormone Analogs

• Digoxin: Hypercalcemia, which can be induced by PTH analogs, may potentiate the risk of digitalis toxicity.
• Other Drugs that May Cause Hypercalcemia: Concurrent use with thiazide diuretics (which reduce urinary calcium excretion) or high doses of calcium/vitamin D may increase the risk of hypercalcemia.
• Contraindications: Hypercalcemia; pre-existing skeletal malignancies or bone metastases; prior radiation therapy to the skeleton; metabolic bone diseases other than osteoporosis (e.g., Paget’s disease); unexplained elevations of alkaline phosphatase; pediatric patients and young adults with open epiphyses; pregnancy.

Special Considerations

Pregnancy and Lactation

Bisphosphonates: Pregnancy Category C (US) or D (Australia). Bisphosphonates cross the placenta and incorporate into the fetal skeleton. Animal studies have shown fetal skeletal abnormalities. Because bisphosphonates persist in bone for years, they may be present during a subsequent pregnancy even if therapy is discontinued. Use during pregnancy is generally avoided unless the potential benefit to the mother outweighs the potential risk to the fetus. They are not recommended during lactation.

Parathyroid Hormone Analogs: Pregnancy Category C. Animal studies have shown fetal toxicity. Teriparatide and abaloparatide are contraindicated during pregnancy and should not be used by nursing mothers.

Pediatric and Geriatric Considerations

Pediatric: Bisphosphonates (primarily intravenous pamidronate) are used off-label for osteogenesis imperfecta and other pediatric bone disorders under specialist supervision. Their use requires careful monitoring of growth and bone metabolism. PTH analogs are contraindicated in pediatric patients due to the theoretical risk of osteosarcoma and because their safety and efficacy have not been established.

Geriatric: This is the primary population for these therapies. Considerations include:

• Increased prevalence of renal impairment, necessitating dose adjustment or choice of agent.
• Higher risk of vitamin D deficiency and secondary hyperparathyroidism, which must be corrected before initiating therapy.
• Greater susceptibility to hypocalcemia, orthostatic hypotension (with PTH), and electrolyte disturbances.
• Polypharmacy, increasing the risk of drug interactions, especially with oral bisphosphonates.
• Comorbid conditions that may affect adherence to complex dosing instructions or self-injection.

Renal and Hepatic Impairment

Renal Impairment:

• Bisphosphonates: Renal clearance is the primary route of elimination for the unbound fraction. For oral bisphosphonates, use is not recommended when CrCl is < 30-35 mL/min due to lack of data and increased risk of accumulation. For intravenous bisphosphonates, dose reduction or infusion rate adjustment is required based on CrCl. Zoledronate, for example, is contraindicated in severe renal impairment (CrCl < 35 mL/min) for the osteoporosis indication. Adequate hydration is critical before IV administration.
• Parathyroid Hormone Analogs: No dosage adjustment is required for mild to moderate renal impairment. Use with caution in severe renal impairment (CrCl < 30 mL/min) due to reduced clearance and potential for hypercalcemia. They are not recommended in patients with end-stage renal disease on dialysis.

Hepatic Impairment: No specific dosage adjustments are required for either class based on hepatic impairment. Bisphosphonates are not metabolized by the liver. PTH analogs are metabolized by non-specific peptidases, and their pharmacokinetics are not significantly altered in liver disease.

Summary/Key Points

• Bisphosphonates and PTH analogs are cornerstone therapies for disorders of calcium balance and bone metabolism, primarily osteoporosis, acting via opposing effects on bone remodeling: anti-resorptive and anabolic, respectively.
• The mechanism of bisphosphonates involves high-affinity binding to bone mineral, selective uptake by osteoclasts, and intracellular inhibition of resorption—either via cytotoxic ATP analogs (non-N-BPs) or inhibition of the mevalonate pathway enzyme FPPS (N-BPs), leading to osteoclast apoptosis.
• PTH analogs (teriparatide, abaloparatide) exert an anabolic effect through intermittent activation of the PTH1R on osteoblasts, stimulating bone formation and, to a lesser degree, coupled bone resorption.
• Bisphosphonate pharmacokinetics are defined by very low oral bioavailability (requiring strict fasting administration), extensive skeletal binding with an extremely long skeletal half-life (months to years), and renal excretion. PTH analogs have high subcutaneous bioavailability, a short plasma half-life (~1 hour), and are cleared by non-specific peptidase degradation.
• Major clinical indications include osteoporosis (both classes), Paget’s disease and hypercalcemia of malignancy (bisphosphonates), and high-fracture-risk osteoporosis (PTH analogs).
• Significant adverse effects of bisphosphonates include osteonecrosis of the jaw, atypical femoral fractures (both associated with long-term use), acute-phase reactions (IV), and GI intolerance (oral). PTH analogs carry a black box warning for osteosarcoma (based on rodent data) and can cause transient hypercalcemia and orthostatic hypotension.
• Important drug interactions for bisphosphonates involve cations that impair absorption; for PTH analogs, interactions primarily relate to additive hypercalcemic effects.
• Special considerations are crucial: bisphosphonates require dose adjustment in renal impairment and are generally avoided in pregnancy; PTH analogs are contraindicated in pregnancy, pediatric use, and in patients at increased risk for osteosarcoma.

Clinical Pearls

• Always assess and replete vitamin D and calcium status before initiating any therapy for osteoporosis to prevent hypocalcemia and ensure optimal drug effect.
• Consider a “drug holiday” after 3-5 years of oral bisphosphonate therapy or after 3 annual infusions of zoledronate for patients at lower fracture risk, to potentially mitigate the risk of AFFs while maintaining some anti-fracture benefit due to skeletal retention.
• Anabolic therapy with a PTH analog should generally be followed by an anti-resorptive agent (e.g., a bisphosphonate) to consolidate the gained bone mass.
• A comprehensive dental examination and any necessary invasive procedures should be completed before initiating high-dose IV bisphosphonate therapy in oncology patients to minimize ONJ risk.
• Patient education on proper administration technique for oral bisphosphonates (upright with water, fasting) is critical for efficacy and tolerability.

References

1. Rang HP, Ritter JM, Flower RJ, Henderson G. Rang & Dale's Pharmacology. 9th ed. Edinburgh: Elsevier; 2020.
2. Whalen K, Finkel R, Panavelil TA. Lippincott Illustrated Reviews: Pharmacology. 7th ed. Philadelphia: Wolters Kluwer; 2019.
3. Trevor AJ, Katzung BG, Kruidering-Hall M. Katzung & Trevor's Pharmacology: Examination & Board Review. 13th ed. New York: McGraw-Hill Education; 2022.
4. Brunton LL, Hilal-Dandan R, Knollmann BC. Goodman & Gilman's The Pharmacological Basis of Therapeutics. 14th ed. New York: McGraw-Hill Education; 2023.
5. Katzung BG, Vanderah TW. Basic & Clinical Pharmacology. 15th ed. New York: McGraw-Hill Education; 2021.
6. Golan DE, Armstrong EJ, Armstrong AW. Principles of Pharmacology: The Pathophysiologic Basis of Drug Therapy. 4th ed. Philadelphia: Wolters Kluwer; 2017.
7. Rang HP, Ritter JM, Flower RJ, Henderson G. Rang & Dale's Pharmacology. 9th ed. Edinburgh: Elsevier; 2020.
8. Whalen K, Finkel R, Panavelil TA. Lippincott Illustrated Reviews: Pharmacology. 7th ed. Philadelphia: Wolters Kluwer; 2019.