Pharmacology of Drugs Affecting Calcium Balance (Bisphosphonates, PTH)

Introduction/Overview

The regulation of calcium and phosphate homeostasis is a critical physiological process, essential for skeletal integrity, neuromuscular function, and numerous intracellular signaling pathways. Pharmacological intervention in this system is primarily directed towards disorders of bone remodeling, most notably osteoporosis, but also encompasses conditions such as Paget’s disease of bone, hypercalcemia of malignancy, and hypoparathyroidism. Two principal therapeutic classes dominate this domain: the antiresorptive bisphosphonates and the anabolic parathyroid hormone (PTH) analogs. These agents exert opposing effects on bone turnover but share the ultimate goal of increasing bone strength and reducing fracture risk. Their clinical application represents a cornerstone in the management of metabolic bone diseases.

The clinical relevance of these drugs is substantial, given the high prevalence of osteoporosis and its associated morbidity, mortality, and economic burden. Osteoporotic fractures, particularly of the hip and spine, lead to significant pain, disability, loss of independence, and increased mortality. The development and refinement of bisphosphonates and PTH analogs have transformed the therapeutic landscape, offering effective means to prevent bone loss and, in the case of PTH, to stimulate new bone formation. Understanding their distinct and sometimes complementary pharmacologies is imperative for rational, patient-specific therapy.

Learning Objectives

• Compare and contrast the fundamental mechanisms of action of bisphosphonates and parathyroid hormone analogs on bone cell activity and calcium homeostasis.
• Describe the pharmacokinetic properties of oral and intravenous bisphosphonates, including absorption limitations, distribution, and elimination, and relate these to dosing regimens.
• Outline the approved clinical indications, major adverse effects, and important contraindications for both drug classes.
• Analyze the key drug-drug and drug-food interactions associated with bisphosphonate therapy and the implications for patient administration.
• Evaluate special considerations for the use of these agents in populations with renal impairment, in the elderly, and during pregnancy or lactation.

Classification

Drugs affecting calcium balance for skeletal disorders are broadly classified by their primary effect on bone remodeling: antiresorptive agents, which inhibit bone breakdown, and anabolic agents, which stimulate bone formation. The bisphosphonates constitute the major antiresorptive class discussed herein, while teriparatide and abaloparatide represent the anabolic PTH receptor agonist class.

Bisphosphonates

Bisphosphonates are synthetic analogs of inorganic pyrophosphate (P-O-P), where the central oxygen atom is replaced by a carbon, creating a 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 critically determines their potency and precise mechanism of action.

• Non-Nitrogen-Containing Bisphosphonates (First Generation): These agents, such as etidronate and clodronate, are metabolically incorporated into non-hydrolyzable analogs of adenosine triphosphate (ATP), leading to osteoclast apoptosis. Their use is now largely historical or restricted to specific indications like Paget’s disease.
• Nitrogen-Containing Bisphosphonates (Second and Third Generation): This group includes the most widely used agents. The nitrogen moiety in the side chain (often within an alkyl chain or a heterocyclic ring) greatly enhances potency. Examples include:
  • Alendronate, Risedronate, Ibandronate: Often termed amino-bisphosphonates, with linear side chains.
  • Zoledronate (Zoledronic Acid): Contains a heterocyclic imidazole ring, making it the most potent commercially available bisphosphonate.
  • Pamidronate: An earlier intravenous amino-bisphosphonate.

Parathyroid Hormone Analogs

This class consists of recombinant fragments or analogs of human parathyroid hormone (PTH) that act as agonists at the PTH1 receptor.

• Teriparatide: A recombinant formulation of the biologically active N-terminal 1-34 fragment of human PTH.
• Abaloparatide: A synthetic 34-amino acid analog of parathyroid hormone-related protein (PTHrP), engineered for selective PTH1 receptor activation with a modified profile.
• PTH (1-84): The full-length recombinant human PTH, used in some regions for the treatment of hypoparathyroidism rather than osteoporosis.

Mechanism of Action

The mechanisms of action for bisphosphonates and PTH analogs are fundamentally distinct, targeting different phases of the bone remodeling cycle. Bisphosphonates primarily inhibit osteoclast-mediated bone resorption, while PTH analogs stimulate osteoblast-mediated bone formation.

Bisphosphonates: Molecular and Cellular Mechanisms

The action of bisphosphonates is highly selective for bone due to their physicochemical affinity for hydroxyapatite crystals. Following administration, they rapidly bind to exposed bone mineral surfaces, particularly at sites of active resorption where hydroxyapatite is freshly exposed. Osteoclasts then internalize the bisphosphonate during the resorptive process.

Once inside the osteoclast, the mechanism diverges based on chemical structure:

• Non-Nitrogen-Containing Bisphosphonates (e.g., Clodronate, Etidronate): These compounds are metabolically incorporated into non-hydrolyzable analogs of adenosine triphosphate (AppCp-type molecules). The intracellular accumulation of these cytotoxic ATP analogs inhibits mitochondrial adenine nucleotide translocase and other ATP-dependent processes, ultimately inducing osteoclast apoptosis.
• Nitrogen-Containing Bisphosphonates (N-BPs; e.g., Alendronate, Risedronate, Zoledronate): These agents inhibit the mevalonate pathway, a critical biochemical route for the synthesis of sterols (like cholesterol) and isoprenoid lipids. N-BPs potently inhibit the enzyme farnesyl pyrophosphate (FPP) synthase. Inhibition of FPP synthase leads to a depletion of downstream isoprenoid lipids, farnesyl pyrophosphate (FPP) and geranylgeranyl pyrophosphate (GGPP). These lipids are essential for the post-translational prenylation (attachment of lipid chains) of small GTPase signaling proteins such as Ras, Rho, and Rac. Proper membrane localization and function of these GTPases are crucial for osteoclast cytoskeletal organization, membrane ruffling, vesicular trafficking, and cell survival. Without prenylation, these signaling pathways are disrupted, leading to cytoskeletal collapse, loss of the sealing zone and ruffled border (the osteoclast’s resorptive apparatus), and induction of apoptosis.

The net result for both types is a profound reduction in osteoclast number and activity. This inhibition of bone resorption creates a transient positive balance in bone remodeling, as bone formation by osteoblasts continues at least initially at its previous rate. Over time, the reduction in resorption leads to a coupled decrease in bone formation, resulting in a new, lower steady state of bone turnover, favoring a gradual increase in bone mineral density (BMD).

Parathyroid Hormone Analogs: Molecular and Cellular Mechanisms

Teriparatide and abaloparatide are agonists of the PTH1 receptor, a G-protein coupled receptor (GPCR) expressed predominantly on osteoblasts and osteocytes. The pharmacological action of intermittent daily administration contrasts sharply with the continuous elevation of PTH seen in hyperparathyroidism, which is catabolic to bone.

The anabolic effect of intermittent PTH is mediated through complex signaling cascades:

1. Receptor Activation and Signaling: Binding of the ligand to the PTH1 receptor activates multiple G-protein subtypes (primarily G_s and G_q). Activation of G_s stimulates adenylyl cyclase, increasing intracellular cyclic AMP (cAMP) and activating protein kinase A (PKA). Activation of G_q stimulates phospholipase C, generating inositol trisphosphate (IP₃) and diacylglycerol (DAG), leading to increased intracellular calcium and activation of protein kinase C (PKC).
2. Effects on Osteoblast Lineage Cells: The cAMP/PKA pathway is considered particularly important for the anabolic response. Signaling leads to:
   • Increased differentiation of osteoblast precursors and reduced apoptosis of mature osteoblasts and osteocytes, thereby increasing the number and lifespan of bone-forming cells.
   • Upregulation of growth factor production, notably insulin-like growth factor 1 (IGF-1) and transforming growth factor-beta (TGF-β), which act in an autocrine/paracrine manner to stimulate bone formation.
   • Transient inhibition of sclerostin production by osteocytes. Sclerostin is a potent inhibitor of the Wnt/β-catenin signaling pathway, a master regulator of osteoblast activity. Reduced sclerostin levels thus potentiate Wnt signaling, further stimulating osteoblastogenesis and bone formation.
3. Bone Remodeling Dynamics: Intermittent PTH preferentially stimulates new bone formation on trabecular and cortical surfaces, including periosteal surfaces, leading to improvements in bone microarchitecture, increased bone size, and enhanced bone strength that are distinct from the effects of antiresorptives. It may also stimulate bone remodeling initially, but with a greater effect on formation than resorption.

Abaloparatide has a higher binding affinity for the RG conformation of the PTH1 receptor, which may translate to a more selective anabolic profile with less pronounced effects on bone resorption and calcium mobilization compared to teriparatide, though both are potent anabolic agents.

Pharmacokinetics

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

Bisphosphonates

The pharmacokinetics of bisphosphonates are characterized by very low oral bioavailability, extensive and rapid uptake by bone, and renal elimination of unbound drug.

• Absorption: Oral bioavailability is generally poor, ranging from less than 1% for alendronate and risedronate to approximately 0.6% for ibandronate and 0.7% for risedronate. Absorption occurs primarily in the upper small intestine via paracellular transport and is severely impaired by food, beverages (especially coffee and orange juice), and divalent cations (Ca²⁺, Mg²⁺, Fe²⁺, Al³⁺) which form insoluble complexes with the bisphosphonate. Therefore, oral bisphosphonates must be taken after an overnight fast with plain water only, and the patient must remain upright and fast for at least 30-60 minutes afterward.
• Distribution: Plasma protein binding is variable but generally low (e.g., approximately 78% for alendronate). The drugs distribute rapidly into a central compartment and then exhibit multiphasic elimination. The primary determinant of distribution is chemisorption to hydroxyapatite bone mineral. The fraction of dose bound to bone is estimated to be 20-80%, depending on the agent, dose, and skeletal turnover rate. Binding is highest at sites of active remodeling. Soft tissue distribution is minimal.
• Metabolism: Bisphosphonates are not metabolized hepatically. Non-nitrogen-containing bisphosphonates can be intracellularly metabolized to cytotoxic ATP analogs, as described in their mechanism. Nitrogen-containing bisphosphonates are not metabolized.
• Excretion: Unbound drug in plasma is excreted unchanged by the kidneys via glomerular filtration and possibly active tubular secretion. The terminal elimination half-life from the body is extremely long (months to years) and reflects the slow release of bisphosphonate from the bone reservoir back into the systemic circulation, followed by renal excretion. This skeletal retention underpins the prolonged duration of action, allowing for intermittent dosing (e.g., weekly, monthly, or even yearly).
• Dosing Considerations: The long skeletal half-life permits infrequent dosing. Standard regimens include daily, weekly (alendronate, risedronate), monthly (ibandronate, risedronate), quarterly intravenous (ibandronate), or yearly intravenous (zoledronate) administration. Intravenous administration bypasses the absorption issues and is used for patients intolerant of oral therapy, with malabsorption, or requiring rapid effect (as in hypercalcemia of malignancy).

Parathyroid Hormone Analogs

Teriparatide and abaloparatide are administered as daily subcutaneous injections, reflecting their peptide nature and short plasma half-life.

• Absorption: Following subcutaneous injection, absorption is rapid. Teriparatide reaches peak plasma concentration (C_max) in approximately 30 minutes. Bioavailability is estimated to be 95%.
• Distribution: The volume of distribution is limited, approximately 0.12-0.17 L/kg for teriparatide, consistent with distribution into extracellular fluid. They do not accumulate in bone or other tissues in a pharmacologically active form.
• Metabolism: Metabolism occurs primarily via non-specific enzymatic degradation (e.g., by proteases) in the liver and possibly at extrahepatic sites. The fragments are subsequently cleared by the renal system. Hepatic cytochrome P450 enzymes are not involved.
• Excretion: Elimination is rapid. Teriparatide is cleared from the systemic circulation with a terminal half-life (t_1/2) of approximately 1 hour when administered subcutaneously, primarily via hepatic and renal clearance. The anabolic effect on bone is sustained despite the short plasma exposure due to the activation of longer-lasting intracellular signaling cascades in osteoblasts.
• Dosing Considerations: The recommended regimen is a single daily subcutaneous injection for a finite period (up to 24 months for teriparatide and abaloparatide in osteoporosis) due to safety concerns regarding long-term use. The injection can be administered at any time of day without regard to meals, though consistency is advised.

Therapeutic Uses/Clinical Applications

The primary applications for these agents are in the management of metabolic bone diseases characterized by compromised bone strength.

Bisphosphonates

• Osteoporosis (Postmenopausal, Male, and Glucocorticoid-Induced): This is the most common indication. Bisphosphonates are first-line agents for the treatment and prevention of osteoporosis. They significantly reduce the risk of vertebral fractures (by 40-70%) and, for some agents (alendronate, risedronate, zoledronate), non-vertebral and hip fractures.
• Paget’s Disease of Bone: Bisphosphonates, particularly potent intravenous zoledronate or oral risedronate, are the treatment of choice to suppress the excessively high bone turnover, alleviate bone pain, and prevent complications like deformity, fracture, and neurological compression.
• Hypercalcemia of Malignancy: Intravenous bisphosphonates (pamidronate, zoledronate) are highly effective in lowering serum calcium levels by inhibiting osteoclast-mediated bone resorption induced by tumor-derived factors.
• Prevention and Treatment of Bone Metastases (Solid Tumors and Multiple Myeloma): Intravenous bisphosphonates (zoledronate, pamidronate) and the RANKL inhibitor denosumab (a distinct antiresorptive) are used to reduce skeletal-related events (SREs) such as pathologic fractures, spinal cord compression, and the need for radiation or surgery to bone in patients with bone metastases.
• Osteogenesis Imperfecta: Intravenous pamidronate or oral bisphosphonates are used in children and adults to increase bone density, reduce fracture frequency, and decrease bone pain.

Parathyroid Hormone Analogs

• Osteoporosis in Postmenopausal Women and Men at High Risk for Fracture: Teriparatide and abaloparatide are indicated for the treatment of severe osteoporosis in individuals who have failed or are intolerant to other therapies, or who are at very high fracture risk (e.g., those with multiple fractures or very low BMD). They are particularly effective at reducing vertebral and non-vertebral fractures. Their anabolic action makes them suitable for individuals with very low bone formation.
• Glucocorticoid-Induced Osteoporosis: Teriparatide is approved for the treatment of men and women with glucocorticoid-induced osteoporosis at high risk for fracture. It has been shown to be superior to alendronate in increasing BMD in this population.
• Hypoparathyroidism: Recombinant human PTH(1-84) (not teriparatide) is approved as hormone replacement therapy to control hypocalcemia in patients with chronic hypoparathyroidism who cannot be well-controlled on conventional therapy (calcium and active vitamin D).

Adverse Effects

The adverse effect profiles of these drug classes reflect their different mechanisms and routes of administration.

Bisphosphonates

• Gastrointestinal Effects (Oral Agents): Upper GI irritation, including esophagitis, esophageal ulcers, dyspepsia, and abdominal pain, is common. Adherence to dosing instructions (upright posture, adequate water) is critical to minimize risk.
• Acute-Phase Reaction (Intravenous, especially Zoledronate): A transient flu-like syndrome (fever, myalgia, arthralgia, headache) occurs in 10-40% of patients after the first infusion, likely due to cytokine release (e.g., IL-6, TNF-α) from activated γδ T cells. It is self-limiting, rarely recurs with subsequent doses, and can be mitigated with acetaminophen or NSAIDs.
• Renal Impairment: Intravenous bisphosphonates, particularly when infused too rapidly or in patients with pre-existing renal insufficiency, can cause acute kidney injury, typically manifesting as acute tubular necrosis or collapsing focal segmental glomerulosclerosis. Renal function must be assessed prior to each IV dose.
• Osteonecrosis of the Jaw (ONJ): This is a rare but serious condition characterized by exposed, necrotic bone in the maxillofacial region that fails to heal over 8 weeks in a patient with no history of radiation to the jaw. Risk is highest with high-dose IV therapy for malignancy (estimated incidence 1-10%), and much lower with oral osteoporosis therapy (<0.1%). Risk factors include invasive dental procedures, poor oral hygiene, and concomitant antiangiogenic therapy. Preventive dental care is paramount.
• 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. The absolute risk is low but increases with longer duration of therapy (>3-5 years). Pathophysiology may involve oversuppression of bone turnover, leading to impaired microdamage repair and altered bone material properties. A drug holiday may be considered after 3-5 years of therapy in lower-risk patients.
• Hypocalcemia: Particularly a risk after the first IV dose in patients with vitamin D deficiency or hypoparathyroidism. Adequate calcium and vitamin D supplementation is mandatory.
• Ocular Inflammation: Rare reports of uveitis, scleritis, and episcleritis.

Parathyroid Hormone Analogs

• Hypercalcemia and Hypercalciuria: Transient, mild increases in serum and urinary calcium are common, especially several hours after injection. Monitoring of serum calcium is recommended.
• Orthostatic Hypotension: Teriparatide can cause a transient decrease in blood pressure, sometimes with dizziness or tachycardia, within the first several hours after injection. The initial dose should be administered in a setting where the patient can sit or lie down if needed.
• Leg Cramps and Dizziness: Commonly reported.
• Increased Serum Uric Acid: Mild elevations may occur.
• Black Box Warning – Osteosarcoma: Rodent toxicology studies with teriparatide demonstrated a dose-dependent increase in the incidence of osteosarcoma. This risk appears to be specific to the rodent model (rapidly growing skeletons) and has not been observed in human clinical trials or post-marketing surveillance over nearly two decades. Nevertheless, a black box warning exists, and use is contraindicated in patients at increased baseline risk for osteosarcoma, including those with Paget’s disease of bone, unexplained elevations of alkaline phosphatase, open epiphyses, or prior skeletal radiation.
• Nausea and Headache: These are relatively common but often transient side effects.

Drug Interactions

Significant interactions are more prominent with bisphosphonates due to their administration requirements and renal elimination.

Bisphosphonates

• Divalent and Trivalent Cations (Drug-Food Interaction): Calcium, magnesium, iron, and aluminum (found in supplements, antacids, and food) form insoluble complexes with oral bisphosphonates, preventing absorption. Administration must be separated by at least 30-60 minutes, preferably longer.
• Other Oral Medications: Any medication that can irritate the esophagus (e.g., NSAIDs, doxycycline) may have an additive irritant effect. Other oral medications should generally be taken at a different time of day to avoid interfering with bisphosphonate absorption.
• Aminoglycosides and Loop Diuretics: Concomitant use with intravenous bisphosphonates may potentiate hypocalcemia.
• Nephrotoxic Drugs (e.g., NSAIDs, Contrast Dye): Concurrent use may increase the risk of renal impairment with intravenous bisphosphonates. Caution and monitoring are advised.
• Contraindications: Oral bisphosphonates are contraindicated in patients with abnormalities of the esophagus that delay emptying (e.g., achalasia, stricture), inability to stand or sit upright for 30-60 minutes, or hypocalcemia. Intravenous bisphosphonates are contraindicated in patients with severe renal impairment (e.g., creatinine clearance <30-35 mL/min for zoledronate).

Parathyroid Hormone Analogs

Formal drug-drug interactions are less common due to peptide metabolism and renal clearance.

• Digoxin: Hypercalcemia may predispose patients to digitalis toxicity. Serum calcium and digoxin levels should be monitored.
• Other Drugs Affecting Calcium Metabolism: Concurrent use with high-dose vitamin D, calcium supplements, or thiazide diuretics (which reduce calcium excretion) may increase the risk of hypercalcemia. Monitoring is warranted.
• Contraindications: As per the black box warning, contraindications include a history of skeletal radiation, Paget’s disease of bone, unexplained elevated alkaline phosphatase, open epiphyses, bone metastases, or a history of metabolic bone disease other than osteoporosis. Use is also contraindicated in pregnancy.

Special Considerations

Pregnancy and Lactation

Bisphosphonates: Pregnancy Category C (D for intravenous use in malignancy). Bisphosphonates cross the placenta and are incorporated into the fetal skeleton. Animal studies have shown fetal skeletal abnormalities. Because bisphosphonates persist in bone for years, there is a theoretical risk to a developing fetus even if therapy is discontinued prior to conception. Use during pregnancy is generally avoided unless the potential benefit outweighs the significant risk. Use during lactation is not recommended due to the potential for secretion into breast milk and accumulation in the infant’s skeleton.

Parathyroid Hormone Analogs: Pregnancy Category C. Teriparatide and abaloparatide are contraindicated during pregnancy and lactation due to the lack of safety data and the theoretical risk based on the rodent osteosarcoma findings.

Pediatric and Geriatric Use

Pediatric: Bisphosphonates (primarily pamidronate) are used off-label for osteogenesis imperfecta and other pediatric bone disorders under specialist supervision. PTH analogs are contraindicated in pediatric populations due to the open epiphyses and the osteosarcoma warning. Their safety and efficacy have not been established.

Geriatric: Both classes are extensively used in the elderly. For bisphosphonates, age-related decline in renal function must be considered, especially for intravenous dosing. Adherence to complex oral dosing instructions may be challenging for some elderly patients, making weekly, monthly, or yearly regimens advantageous. For PTH analogs, orthostatic hypotension may be of greater concern in the elderly. The benefits of fracture prevention must be weighed against the practicalities of daily subcutaneous injection.

Renal and Hepatic Impairment

Renal Impairment:

Bisphosphonates: Renal excretion is the primary route of elimination for unbound drug. For oral bisphosphonates, no dosage adjustment is typically needed for mild-to-moderate impairment, as the poorly absorbed fraction is excreted in feces. However, they are often avoided in severe renal impairment (CrCl <30-35 mL/min) due to lack of safety data and potential for electrolyte disturbances. For intravenous bisphosphonates, dosage adjustment or infusion rate extension is required based on creatinine clearance. Zoledronate is contraindicated in severe renal impairment (CrCl <35 mL/min) or in patients with evidence of acute renal impairment.

PTH Analogs: Teriparatide exposure may be increased in patients with renal or hepatic impairment, but no specific dosage adjustment is recommended. However, caution is advised in patients with severe impairment due to the potential for altered calcium handling.

Hepatic Impairment:

Bisphosphonates: No dosage adjustment is required, as they are not hepatically metabolized.

PTH Analogs: Formal studies are lacking. Since metabolism involves non-specific proteolytic degradation, significant hepatic impairment could potentially alter clearance. Caution is advised, but no specific dosage recommendations exist.

Summary/Key Points

• Bisphosphonates and PTH analogs are cornerstone therapies for osteoporosis and other bone disorders, acting via inhibition of bone resorption and stimulation of bone formation, respectively.
• Nitrogen-containing bisphosphonates (alendronate, risedronate, zoledronate) exert their potent antiresorptive effect by inhibiting the mevalonate pathway enzyme FPP synthase in osteoclasts, disrupting prenylation of signaling proteins and inducing apoptosis.
• Teriparatide and abaloparatide are anabolic PTH1 receptor agonists. Their intermittent daily administration activates cAMP/PKA and other pathways in osteoblasts, increasing their differentiation and lifespan while transiently inhibiting sclerostin, leading to net bone formation.
• Oral bisphosphonate absorption is very low (<1%) and severely impaired by food and divalent cations, necessitating strict fasting administration. They have an extremely long skeletal half-life, permitting infrequent dosing. PTH analogs have a short plasma half-life (~1 hour) and require daily subcutaneous injection.
• Major clinical uses include osteoporosis (both classes), Paget’s disease and hypercalcemia of malignancy (bisphosphonates), and high-risk osteoporosis (PTH analogs).
• Key adverse effects for bisphosphonates include upper GI irritation (oral), acute-phase reactions (IV), osteonecrosis of the jaw, and atypical femoral fractures. For PTH analogs, transient hypercalcemia, orthostatic hypotension, and a theoretical risk of osteosarcoma (per black box warning) are notable.
• Oral bisphosphonates have critical interactions with calcium, iron, and antacids. Both classes require caution in renal impairment, and neither is recommended during pregnancy or lactation.

Clinical Pearls

• Ensure patients taking oral bisphosphonates are adequately supplemented with calcium (1200 mg/day) and vitamin D (800-2000 IU/day) to prevent hypocalcemia and optimize therapeutic response.
• Consider a “drug holiday” after 3-5 years of oral bisphosphonate therapy for osteoporosis in patients at lower fracture risk, to potentially mitigate the risk of atypical femoral fractures while maintaining some anti-fracture benefit due to skeletal retention of the drug.
• PTH analog therapy is generally limited to 24 months lifetime use. Sequential therapy with an antiresorptive agent (e.g., a bisphosphonate or denosumab) after completing a PTH analog course is recommended to consolidate and maintain the gained bone mineral density.
• A dental examination and preventive care should be considered prior to initiating high-dose intravenous bisphosphonate therapy for malignancy to reduce ONJ risk. For osteoporosis doses, maintaining good oral hygiene and routine dental care is sufficient.
• Monitoring of therapy typically involves assessment of bone mineral density by DXA scan every 1-2 years and measurement of bone turnover markers (e.g., serum C-telopeptide, CTX) which show a rapid decline with bisphosphonates and an initial rise followed by a decline with PTH analogs.

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