Discover effective integrative treatment strategies for hyperparathyroidism that can enhance your health and quality of life.

Abstract: A Modern Perspective on a Common Endocrine Disorder

Hyperparathyroidism is one of the most commonly encountered yet frequently misunderstood endocrine disorders in clinical practice. This educational post explores the intricate hormonal and metabolic relationships that define hyperparathyroidism, drawing on the latest evidence-based research and clinical findings from leading endocrine specialists. As a Doctor of Chiropractic, Board-Certified Family Nurse Practitioner, and Certified Functional Medicine Practitioner, my perspective is rooted in a holistic and integrative understanding of the human body. At the heart of this condition lies a triad of interrelated factors: calcium regulation, vitamin D metabolism, and parathyroid hormone (PTH) secretion. Understanding how these three elements interact—and what happens when they fall out of balance—is essential for any clinician seeking to provide comprehensive, integrative care.

This post begins with the fundamental anatomy of the parathyroid glands, tracing the historical discovery of hyperparathyroidism back to 1926 and the fascinating case of Captain Charles Martel, whose story illustrates how dramatically this condition can affect skeletal and renal health. From there, we move into the physiological roles of calcium in the human body, the nuanced differences between total serum calcium, ionized calcium, and albumin-bound calcium, and why these distinctions matter enormously in clinical decision-making. We then explore vitamin D in depth—its two major supplemental forms (D2 and D3), its dietary and sun-derived sources, and its critical conversion to the active hormone calcitriol, which governs intestinal calcium absorption and renal calcium retention. The post continues with a thorough discussion of parathyroid hormone, its physiological function in maintaining calcium and phosphorus homeostasis, and what happens when PTH levels rise too high or fall too low.

The symptoms of hypercalcemia are discussed in clinical detail, ranging from the subtle and asymptomatic presentations seen at mildly elevated calcium levels to the profoundly dangerous presentations that emerge at higher thresholds—including altered mental status, acute kidney injury, and severe dehydration. Throughout, case studies from our clinic are incorporated to help ground the physiological principles in real-world clinical scenarios, including the critical decision-making process between surgical intervention and watchful observation, supported by long-term, randomized controlled trials.

This educational resource also explores how the integrative, multidisciplinary approach practiced at Injury Medical Clinic PA in El Paso, Texas—led by myself, Dr. Alexander Jimenez, and supported by Medical Director Dr. Maria Guadalupe Cardenas, MD, Board Certified in Internal Medicine with over 40 years of clinical experience—provides patients with a uniquely comprehensive framework for managing complex endocrine and metabolic disorders like hyperparathyroidism. Integrative chiropractic care, functional medicine, internal medicine oversight, rehabilitation, and personal injury care combine to address the full spectrum of this condition’s effects on the musculoskeletal, renal, gastrointestinal, and neurological systems. Whether you are a clinician, a patient, or a health-conscious individual seeking to understand the calcium-PTH axis more deeply, this post will take you on a thorough, evidence-based journey through one of endocrinology’s most nuanced and clinically significant conditions.

Our Integrative Care Model: A Synergy of Expertise

In my years of clinical practice as both a Doctor of Chiropractic and an Advanced Practice Registered Nurse with board certification in Family Practice (FNP-BC), I have come to appreciate that the human body operates as a beautifully orchestrated system of checks and balances. Nowhere is this more apparent than in the regulation of calcium homeostasis. Calcium is not merely a mineral found in dairy products or bone supplements—it is a critical signaling molecule that governs cardiac conduction, neuromuscular function, hormonal secretion, blood coagulation, and skeletal integrity. When the systems that regulate calcium become dysregulated, the consequences cascade across virtually every organ system in the body.

Hyperparathyroidism is the clinical condition that emerges when the parathyroid glands produce too much parathyroid hormone (PTH), leading to elevated serum calcium levels and a broad spectrum of symptoms that can range from silent and subclinical to acutely life-threatening. As a condition that affects approximately 100,000 new patients per year in the United States (Bilezikian et al., 2022), primary hyperparathyroidism is among the most prevalent endocrine disorders encountered in outpatient practice—yet it remains frequently overlooked, misdiagnosed, or inadequately managed.

At Injury Medical Clinic PA, also known as Mission Plaza Injury Medical Clinic, we have pioneered a multidisciplinary approach in El Paso, Texas, that places the patient at the center of their care. Our team operates on the principle that complex health issues, especially those stemming from injuries or chronic conditions like hyperparathyroidism, require a multifaceted strategy. The foundation of this approach is the collaboration between me and our esteemed Medical Director and Collaborative Physician, Dr. Maria Guadalupe Cardenas, MD. Dr. Cardenas is a Board Certified Internist with over 40 years of experience in internal medicine (NPI #1164426749, Texas MD License #J2933). Her depth of clinical knowledge in the diagnosis and management of complex systemic diseases—including endocrine disorders, metabolic syndrome, cardiovascular disease, and renal disease—provides the medical foundation upon which our integrative practice is built. This collaborative setup, where an MD provides medical direction alongside a chiropractor, is a cornerstone of modern integrative and injury care clinics.

• Dr. Alex Jimenez (Chiropractic and Functional Medicine): My role focuses on the structural and functional aspects of health. Through chiropractic care, I address the biomechanics of the spine and musculoskeletal system, which can be significantly impacted by the metabolic bone changes seen in hyperparathyroidism. As a functional medicine practitioner, I investigate the root causes of dysfunction, analyzing laboratory data, lifestyle factors, and environmental influences to create a comprehensive wellness plan. This involves nutritional guidance, supplementation protocols, and strategies to restore metabolic balance.
• Dr. Maria Guadalupe Cardenas (Internal Medicine): As our Medical Director, Dr. Cardenas brings an indispensable depth of medical knowledge. Her expertise is crucial for managing the complex medical aspects of our patients’ conditions. She provides medical oversight, prescribes and manages pharmaceuticals when necessary (such as cinacalcet or bisphosphonates), interprets complex diagnostic tests, and ensures our treatment plans are safe, effective, and aligned with established medical standards.
• A Unified Team Approach: Our clinic seamlessly integrates these disciplines with personal injury care, rehabilitation, and other related services. For a patient with hyperparathyroidism, this means:

• Cardenas manages the endocrine and metabolic aspects, such as severe hypercalcemia or medication adjustments.
• I, Dr. Jimenez, address the musculoskeletal symptoms like bone pain, muscle weakness, and joint stiffness through targeted chiropractic adjustments and soft tissue therapies. My functional medicine background allows me to support the patient’s nutritional status, especially vitamin D and calcium balance, post-surgically or during medical management.
• Our rehabilitation team designs exercise programs to improve bone density and muscle strength, mitigating the effects of the disease.

This integrated model ensures that all facets of the patient’s health are addressed, leading to more comprehensive and lasting outcomes. In this educational post, I will walk you through the diagnosis and management of hyperparathyroidism as I approach it clinically: with deep respect for the underlying physiology, a commitment to evidence-based medicine, and an integrative mindset that goes beyond simply treating lab numbers.

The Anatomy of the Parathyroid Glands: Small but Mighty

Understanding the Location and Structure of the Parathyroid Glands

One of the most remarkable things about the parathyroid glands is how disproportionately powerful they are relative to their size. Each of the four parathyroid glands is approximately the size of a grain of rice or a small pea—measuring roughly 3 to 5 millimeters in diameter and weighing only 30 to 40 milligrams (Bilezikian et al., 2022). Yet these four tiny glands, two positioned on the left lobe of the thyroid and two on the right lobe, exercise enormous control over the body’s calcium and phosphorus homeostasis.

The parathyroid glands are posterior to the thyroid gland and are typically found embedded within or closely adherent to the thyroid capsule. However, their anatomical location can vary considerably from person to person. In some individuals, one or more parathyroid glands may be ectopic, meaning they are located in unusual positions such as within the thymus, the mediastinum, or even the carotid sheath. This anatomical variability has important clinical implications, particularly when surgical exploration is being considered for the management of hyperparathyroidism (Delellis et al., 2022).

The chief cells are the primary secretory cells of the parathyroid glands, and they are responsible for producing and releasing parathyroid hormone (PTH). These cells are exquisitely sensitive to changes in serum calcium concentration, and they respond within seconds to minutes to falling calcium levels by increasing PTH secretion. Oxyphil cells are also present in the parathyroid glands, though their precise function is not entirely understood; they become more numerous with advancing age (Bilezikian et al., 2022).

Historical Context: The Discovery of Hyperparathyroidism

The story of how hyperparathyroidism was first identified as a clinical entity is one of the most fascinating and sobering in the history of medicine. The first confirmed diagnosis of hyperparathyroidism was made in 1926 by Dr. Eugene Dubois, whose patient was a merchant mariner named Captain Charles Martel. Captain Martel’s case is historically significant because it illustrates, in dramatic and tragic detail, just how profoundly hyperparathyroidism can ravage the human body when it goes undiagnosed for years.

Captain Martel suffered from a constellation of debilitating symptoms that, viewed through a modern clinical lens, form a textbook picture of primary hyperparathyroidism with severe skeletal and renal involvement. He experienced profound skeletal deterioration, with bones that became progressively weakened, deformed, and painful—a manifestation of what we now call osteitis fibrosa cystica, the most severe skeletal complication of long-standing hyperparathyroidism. He also had longstanding urinary calculi (kidney stones), which were a major and recurring source of suffering throughout his illness. Photographs of Captain Martel taken at different stages of his illness, which can be found with a search of his name, visually document the extraordinary physical transformation that unfolded over the course of his disease.

Captain Martel underwent seven surgical operations before the underlying cause of his illness was finally identified. It was only after this seventh operation that surgeons discovered a parathyroid adenoma—a benign tumor of one of the parathyroid glands that had been driving his catastrophic hypercalcemia for years. Tragically, the complications of his urinary calculi ultimately proved fatal, and Captain Martel died shortly after the adenoma was finally removed. His case remains a powerful reminder of why early diagnosis and prompt management of hyperparathyroidism are so essential.

Today, with routine serum calcium screening as part of standard metabolic panels, the presentation of hyperparathyroidism has shifted dramatically. The majority of patients diagnosed with primary hyperparathyroidism in the modern era are asymptomatic at the time of diagnosis, with the condition discovered incidentally on routine laboratory work (Bilezikian et al., 2022). This shift represents one of the most important advances in endocrinological care—the ability to identify and intervene in a disease process before it reaches the devastating stage that Captain Martel experienced.

The Three Pillars of Hyperparathyroidism: Calcium, Vitamin D, and PTH

The Physiological Roles of Calcium in the Human Body

Calcium is the most abundant mineral in the human body, with approximately 99% of total body calcium stored in the bones and teeth in the form of hydroxyapatite crystals, which provide structural rigidity and strength (Peacock, 2010). The remaining 1% of calcium is distributed between the intracellular compartment (approximately 0.9%) and the extracellular fluid, including the bloodstream (approximately 0.1%). Despite representing only a tiny fraction of total body calcium, this extracellular, circulating calcium pool is tightly regulated and physiologically critical.

In clinical practice, I find that many patients and even some clinicians underestimate the breadth of calcium’s physiological roles. Calcium is not simply a “bone mineral”—it is a universal second messenger and cofactor that participates in an extraordinary range of biological processes:

• Cardiac function and rhythm: Calcium is essential for cardiac muscle contraction and plays a central role in the cardiac action potential. The slow inward calcium current during the plateau phase of the cardiac action potential maintains the prolonged depolarization that characterizes cardiac muscle and prevents tetanic contraction. Hypercalcemia can shorten the QT interval on an electrocardiogram, increasing the risk of arrhythmias, while hypocalcemia can prolong the QT interval, increasing the risk of torsades de pointes (Levis & Bhimji, 2023).
• Neuromuscular transmission: Calcium ions are required for the release of neurotransmitters from presynaptic nerve terminals at the neuromuscular junction. When extracellular calcium falls below normal levels, the threshold for neuronal firing decreases, leading to spontaneous depolarization and the muscle spasms and tetany characteristic of hypocalcemia. Conversely, elevated calcium stabilizes the neuronal membrane and can reduce neuromuscular excitability.
• Nerve signaling: Beyond the neuromuscular junction, calcium participates in intracellular signal transduction cascades throughout the nervous system, modulating synaptic plasticity, neurotransmitter synthesis, and axonal growth.
• Blood coagulation: Calcium (Factor IV in the coagulation cascade) is essential for multiple steps in both the intrinsic and extrinsic coagulation pathways. It acts as a cofactor for the activation of several clotting factors, including Factor X and prothrombin. Without adequate ionized calcium, blood will not clot properly—a principle exploited in blood banking, where calcium is chelated with citrate or EDTA to prevent clotted blood samples (Peacock, 2010).
• Muscle contraction: In both skeletal and smooth muscle, the binding of calcium to troponin C (in skeletal muscle) or calmodulin (in smooth muscle) initiates the cross-bridge cycling between actin and myosin that produces muscle contraction. Without calcium, muscle fibers cannot shorten, and normal movement and organ function would be impossible.
• Enzyme activation: Calcium is a required cofactor for numerous enzymes involved in digestion (including pancreatic lipase and amylase), cellular signaling (including protein kinase C), and apoptosis (programmed cell death).
• Hormone secretion: Calcium-dependent exocytosis is the mechanism by which many endocrine cells release their hormones into the bloodstream, including insulin from pancreatic beta cells and PTH from parathyroid chief cells.

Given this remarkable breadth of physiological function, it is not difficult to understand why even modest disruptions in calcium homeostasis can produce such a wide variety of clinical symptoms—from subtle cognitive changes and muscle weakness to life-threatening cardiac arrhythmias.

Calcium Binding to Albumin and the Concept of Pseudohypocalcemia

In the bloodstream, total serum calcium exists in three forms:

1. Protein-bound calcium (approximately 40-45% of total): The majority of protein-bound calcium is bound to albumin, with a smaller fraction bound to globulins and other plasma proteins. This fraction is biologically inactive.
2. Complexed calcium (approximately 10-15% of total): Calcium forms complexes with anions such as bicarbonate, phosphate, and citrate. This fraction is also biologically inactive.
3. Ionized (free) calcium (approximately 45-50% of total): This is the biologically active fraction of serum calcium—the form that activates calcium-sensing receptors, drives cellular signaling, and is tightly regulated by PTH and calcitriol. It is the ionized calcium level that the parathyroid glands monitor and respond to (Peacock, 2010).

When clinicians measure a total serum calcium level on a standard metabolic panel, they are measuring all three fractions combined. This creates an important clinical pitfall: because such a large fraction of circulating calcium is bound to albumin, any condition that lowers serum albumin will also appear to lower total serum calcium—even if the biologically active ionized calcium fraction remains perfectly normal. This phenomenon is called pseudohypocalcemia.

Pseudohypocalcemia is particularly important to recognize in patients with:

• Chronic liver disease (which impairs albumin synthesis)
• Nephrotic syndrome (which causes massive urinary albumin loss)
• Malnutrition or protein-losing enteropathy
• Critical illness (which is commonly associated with hypoalbuminemia due to systemic inflammation and fluid shifts)
• Pregnancy (which is associated with physiological hemodilution and lower albumin levels)

In any of these clinical contexts, a corrected calcium can be calculated using a simple formula: Corrected calcium (mg/dL) = measured total calcium (mg/dL) + 0.8 × (4.0 – measured albumin in g/dL). This correction adjusts the measured calcium level to what it would be if the patient’s albumin were at the normal reference value of 4.0 g/dL (Peacock, 2010).

However, it is important to recognize that even corrected calcium calculations have limitations. Ionized calcium measurement—obtained through a separate laboratory test using a blood gas analyzer that directly measures the free calcium concentration—provides the most accurate assessment of biologically active calcium status, particularly in acutely ill or hospitalized patients where acid-base disturbances may further complicate the interpretation of calcium levels.

Ionized Calcium: The Gold Standard in Certain Clinical Contexts

Ionized calcium is influenced not only by albumin concentration but also by pH. In an alkalotic state (elevated pH), calcium binding to albumin increases, which decreases the ionized calcium fraction and can precipitate symptoms of hypocalcemia even without a change in total calcium. Conversely, in an acidotic state (decreased pH), calcium is released from albumin, increasing the ionized fraction and potentially masking true hypercalcemia. This is why acid-base status must always be considered when interpreting calcium values (Peacock, 2010).

From a practical standpoint in my clinical setting, I find that ionized calcium measurement is most valuable in the following scenarios:

• Critically ill patients with multisystem organ dysfunction
• Post-surgical patients following parathyroid or thyroid surgery
• Patients receiving massive blood transfusions (the citrate preservative in banked blood chelates calcium)
• Neonates with suspected hypocalcemia
• Patients with significant acid-base disorders

Of particular scientific interest is the finding, highlighted in recent endocrine literature, that there is a strong linear relationship between the ionized calcium level and the size of a parathyroid adenoma. This relationship is more robust and statistically significant than the relationship between total serum calcium and adenoma size, suggesting that ionized calcium is a more sensitive marker of the underlying glandular pathology (Bilezikian et al., 2022). In patients in whom primary hyperparathyroidism is suspected but total serum calcium levels are only mildly elevated, checking an ionized calcium may reveal a more significant elevation and a stronger correlation with the degree of parathyroid pathology than the standard test alone.

Vitamin D: The Sunshine Hormone and Its Critical Role in Calcium Homeostasis

The Nature of Vitamin D as a Fat-Soluble Pro-Hormone

Despite being called a “vitamin,” vitamin D is more accurately classified as a pro-hormone. This precursor compound must be metabolically converted to its active form before it can exert its biological effects. Unlike true vitamins, which must be obtained entirely from dietary sources because the body cannot synthesize them, vitamin D can be endogenously synthesized by the human body through a photochemical reaction in the skin—provided that sufficient ultraviolet B (UVB) radiation is available (Holick, 2007).

As a fat-soluble compound, vitamin D is stored in adipose tissue and the liver and can accumulate over time. This fat solubility is a double-edged sword: it allows the body to build up reserves of vitamin D during periods of sun exposure that can sustain circulating levels through periods of low sun exposure, but it also means that vitamin D toxicity from supplementation—while uncommon—is possible, because the body cannot readily excrete excess fat-soluble vitamins through the urine the way it can with water-soluble vitamins like vitamin C and the B vitamins.

Two Sources of Vitamin D: Skin and Diet

Vitamin D enters the body through two primary pathways:

1. Cutaneous (Skin) Synthesis

When the skin is exposed to UVB radiation (wavelength 290-315 nm) from sunlight, a compound called 7-dehydrocholesterol (a precursor of cholesterol present in the skin) undergoes a photochemical conversion to previtamin D3, which is then thermally isomerized to vitamin D3 (cholecalciferol). This cutaneously synthesized vitamin D3 enters the circulation and travels to the liver for the first step of metabolic activation (Holick, 2007).

Numerous factors influence the efficiency of cutaneous vitamin D synthesis

• Latitude and season: UVB radiation is strongest near the equator and during summer months. In northern latitudes (above approximately 37°N), cutaneous vitamin D synthesis may be negligible for several months during the winter.
• Time of day: UVB penetration is greatest when the sun is at its highest point in the sky (typically 10 AM to 3 PM).
• Skin pigmentation: Melanin in darker-pigmented skin absorbs UVB radiation, reducing the efficiency of vitamin D synthesis. Individuals with darker skin tones require significantly longer sun exposure to generate equivalent amounts of vitamin D compared to individuals with lighter skin (Holick, 2007).
• Age: The capacity for cutaneous vitamin D synthesis declines with advancing age, partly because older skin contains lower concentrations of 7-dehydrocholesterol.
• Sunscreen use: Sunscreen with an SPF of 30 or higher can reduce cutaneous vitamin D synthesis by approximately 95%.
• Glass and clothing: UVB radiation does not penetrate glass or most clothing, so indoor workers and individuals who remain covered outdoors cannot synthesize vitamin D through these protected areas.

2. Dietary Sources

Vitamin D is found naturally in very few foods. The most significant dietary sources include:

• Cod liver oil: One of the most concentrated natural sources of vitamin D3, providing approximately 400 to 1,000 IU per teaspoon. While not the most palatable option for many patients, it remains a historically important source that sustained populations in northern climates through long, sun-deprived winters.
• Oily (fatty) fish: Wild-caught salmon, mackerel, herring, sardines, and tuna are among the best dietary sources of vitamin D3. A 4-ounce serving of wild-caught salmon can provide approximately 300 to 1,000 IU of vitamin D3, depending on the species, whether it is wild-caught or farm-raised (wild-caught generally contains more), and the method of preparation (Holick, 2007).
• Fortified foods: Because naturally occurring dietary sources of vitamin D are limited, many countries have implemented fortification programs. In the United States, cow’s milk is routinely fortified with approximately 400 IU of vitamin D per quart. Other commonly fortified foods include orange juice, breakfast cereals, infant formula, and certain dairy alternatives.
• Eggs: Egg yolks contain small amounts of vitamin D3, approximately 20 IU per yolk. While eggs are a nutritious food, the vitamin D content per yolk is too low to meaningfully contribute to vitamin D sufficiency without consuming a very large number of eggs daily.
• Multivitamins: A standard adult multivitamin typically contains 400 to 1,000 IU of vitamin D per tablet, which is sufficient to prevent frank deficiency in most adults with some degree of sun exposure but may be insufficient to correct established vitamin D deficiency.
• Dedicated vitamin D supplements: These range widely in dose, from 400 IU (appropriate for infants and mild supplementation) to 10,000 IU per capsule (used for aggressive repletion of severe deficiency under medical supervision).

Vitamin D3 Versus Vitamin D2: Clinical Differences and Prescribing Considerations

When I counsel patients or write prescriptions for vitamin D supplementation, I routinely explain the distinction between the two major supplemental forms of vitamin D, as this has practical clinical implications.

Vitamin D3 (cholecalciferol) is the form produced naturally in human skin and found in animal-derived food sources. It is structurally identical to the vitamin D that humans synthesize endogenously. Research has consistently demonstrated that vitamin D3 supplementation produces a greater and more sustained increase in serum 25-hydroxyvitamin D levels compared to an equivalent dose of vitamin D2 (Tripkovic et al., 2012). This is because vitamin D3 binds more avidly to the vitamin D-binding protein (DBP) in the circulation, has a longer half-life, and appears to have greater potency in activating vitamin D receptors. For these reasons, vitamin D3 is generally the preferred form for over-the-counter supplementation.

Vitamin D2 (ergocalciferol) is derived from plant sources, particularly fungi and yeast exposed to UVB light. It is structurally similar to vitamin D3 but differs in its side chain, which affects how it is metabolized. Vitamin D2 is the form used in pharmaceutical prescription-strength vitamin D, typically available as 50,000 IU capsules prescribed as a once-weekly dose for 8 to 12 weeks to treat established vitamin D deficiency. After the initial repletion course, patients are typically transitioned to daily maintenance supplementation with vitamin D3.

The choice of vitamin D2 for prescription-strength preparations has historical and regulatory roots rather than evidence-based superiority. Still, the clinical effectiveness of the 50,000 IU weekly regimen is well-established when used as directed (Holick et al., 2011).

The Metabolic Activation of Vitamin D: From Precursor to Active Hormone

Whether obtained from the skin or from the diet, vitamin D in its initial form is biologically inert. It must undergo a two-step metabolic activation process to become the active hormone that exerts its effects on calcium metabolism:

Step 1: Hepatic Hydroxylation

In the liver, vitamin D (whether D2 or D3) is hydroxylated by the enzyme 25-hydroxylase (CYP2R1) to produce 25-hydroxyvitamin D (25(OH)D), also called calcidiol. This is the major circulating form of vitamin D and the form measured by the standard “vitamin D level” blood test. Serum 25(OH)D is the best indicator of overall vitamin D nutritional status, as it reflects both cutaneous synthesis and dietary/supplemental intake and has a relatively long half-life of approximately 2 to 3 weeks (Holick, 2007).

The clinical thresholds for 25(OH)D used in most guidelines are:

• Deficiency: < 20 ng/mL
• Insufficiency: 20-29 ng/mL
• Sufficiency: 30-100 ng/mL
• Toxicity risk: > 150 ng/mL (though toxicity rarely occurs below 200 ng/mL in the absence of underlying granulomatous disease)

Step 2: Renal Hydroxylation

The circulating 25(OH)D travels to the kidneys, where it is further hydroxylated by the enzyme 1-alpha-hydroxylase (CYP27B1) to produce 1,25-dihydroxyvitamin D (1,25(OH)2D), also known as calcitriol. This is the biologically active form of vitamin D. This form binds to the vitamin D receptor (VDR), a nuclear receptor present in virtually every cell of the body. It initiates gene transcription (Holick, 2007).

Several factors tightly regulate renal 1-alpha-hydroxylase activity:

• PTH: Increased PTH stimulates 1-alpha-hydroxylase activity, increasing calcitriol production. This is one of the key mechanisms by which PTH raises serum calcium—by stimulating the kidneys to produce more calcitriol, which in turn drives more calcium absorption from the gut.
• Serum phosphate: Low phosphate stimulates 1-alpha-hydroxylase activity.
• Fibroblast growth factor 23 (FGF-23): Secreted by osteocytes in bone in response to elevated phosphate and calcitriol, FGF-23 inhibits 1-alpha-hydroxylase activity and reduces calcitriol production, forming a negative feedback loop.
• Calcitriol itself: Through a negative feedback mechanism, calcitriol inhibits its own production by suppressing 1-alpha-hydroxylase activity (Holick, 2007).

Calcitriol’s Actions: How Active Vitamin D Raises Serum Calcium

Calcitriol (active vitamin D) raises serum calcium through two primary mechanisms:

1. Intestinal Calcium Absorption

Calcitriol acts on the small intestinal epithelial cells (enterocytes) to upregulate the expression of proteins required for transcellular calcium absorption, including the apical calcium channel TRPV6 and the intracellular calcium-binding protein calbindin-D9k. By increasing the expression of these transport proteins, calcitriol dramatically enhances the efficiency with which the gut absorbs dietary calcium, increasing fractional calcium absorption from approximately 10-15% (in vitamin D-deficient individuals) to 30-40% (in vitamin D-sufficient individuals) (Holick, 2007). This intestinal action of calcitriol is the primary mechanism by which vitamin D status influences serum calcium levels.

2. Renal Calcium Reabsorption

Calcitriol also acts on the distal convoluted tubule of the kidney to upregulate the expression of calcium transport proteins (including TRPV5, calbindin-D28k, and the sodium-calcium exchanger NCX1) that are responsible for the reabsorption of filtered calcium back into the circulation. This reduces urinary calcium loss and helps maintain serum calcium levels. PTH also directly stimulates renal calcium reabsorption through a calcitriol-independent mechanism, so the renal calcium-retaining effects of PTH involve both direct PTH receptor activation and indirect calcitriol-mediated mechanisms (Peacock, 2010).

3. Bone Resorption (at supraphysiological levels)

At high concentrations, calcitriol can stimulate osteoclast-mediated bone resorption, releasing calcium and phosphate from the skeletal matrix into the circulation. However, under normal physiological conditions, calcitriol primarily supports bone formation and mineralization by ensuring adequate availability of calcium and phosphate for hydroxyapatite deposition. In primary hyperparathyroidism, elevated PTH—rather than calcitriol per se—drives the pathological bone resorption seen in this condition.

Parathyroid Hormone: The Master Regulator of Calcium Homeostasis

Synthesis, Structure, and Secretion of PTH

Parathyroid hormone is an 84-amino acid peptide hormone synthesized by the chief cells of the parathyroid glands. It is initially produced as a larger precursor molecule called prepro-PTH (115 amino acids), which is first cleaved to pro-PTH (90 amino acids) in the endoplasmic reticulum, and then to mature PTH (1-84) in the Golgi apparatus (Bilezikian et al., 2022). The biologically active portion of the molecule resides in the N-terminal region (amino acids 1-34), and fragments of PTH circulate in the blood alongside intact PTH (1-84), which has historically complicated the accurate measurement of PTH by older immunoassay techniques.

Modern intact PTH assays (second-generation and third-generation assays) have largely resolved this issue by using antibodies directed against both the N-terminal and C-terminal regions of the molecule, ensuring that only intact, biologically active PTH is measured. The normal reference range for intact PTH is approximately 10 to 65 pg/mL, though reference ranges vary slightly by laboratory (Bilezikian et al., 2022).

The primary stimulus for PTH secretion is a fall in serum ionized calcium, which is detected by the calcium-sensing receptor (CaSR) on the surface of parathyroid chief cells. The CaSR is a G protein-coupled receptor that acts as a biological “calcium thermostat”. When it senses falling ionized calcium, it reduces its inhibitory signaling, allowing the chief cells to increase PTH secretion. When ionized calcium rises (as occurs after a calcium-rich meal or during calcium infusion), CaSR activation increases, which suppresses PTH secretion (Brown & MacLeod, 2001).

This mechanism is elegantly sensitive and fast: PTH secretion can change within seconds to minutes in response to acute changes in serum calcium. The CaSR is also the therapeutic target of a class of drugs called calcimimetics (most notably cinacalcet), which act as positive allosteric modulators of the CaSR—making it more sensitive to calcium and thereby reducing PTH secretion. This pharmacological mechanism is central to the medical management of primary and secondary hyperparathyroidism.

PTH’s Physiological Actions: Raising Calcium and Lowering Phosphate

When PTH is released into the circulation, it acts on three primary target organs—bone, kidney, and intestine (indirectly)—to raise serum calcium and lower serum phosphate:

Actions on Bone:

PTH binds to PTH/PTHrP receptors (PTH1R) on osteoblasts (bone-forming cells) and indirectly stimulates osteoclasts (bone-resorbing cells) through the RANK-RANKL-OPG signaling pathway. Specifically, PTH stimulates osteoblasts to increase their expression of RANKL (receptor activator of nuclear factor kappa-B ligand) while decreasing their secretion of osteoprotegerin (OPG). This decoy receptor normally blocks RANKL. The resulting increase in the RANKL/OPG ratio activates osteoclast precursors. It increases osteoclast activity, leading to resorption of bone matrix and the release of calcium and phosphate into the bloodstream (Bilezikian et al., 2022).

Interestingly, the skeletal effects of PTH are highly dependent on the pattern of PTH exposure. When PTH is elevated continuously (as in primary hyperparathyroidism), the predominant skeletal effect is catabolic bone resorption, leading to decreased bone mineral density and increased fracture risk. However, when PTH is administered as intermittent subcutaneous injections (as with teriparatide or abaloparatide, both synthetic PTH-based anabolic agents used to treat osteoporosis), the effect is predominantly anabolic bone formation, stimulating osteoblast proliferation and increasing bone mass. This paradoxical difference in PTH’s skeletal effects based on exposure pattern—continuous versus pulsatile—is one of the most pharmacologically fascinating phenomena in bone biology.

Actions on the Kidney:

PTH exerts multiple important effects on the kidneys:

• Calcium reabsorption: PTH stimulates calcium reabsorption in the distal convoluted tubule and connecting tubule, reducing urinary calcium excretion and retaining calcium within the body. This is a direct, calcitriol-independent effect mediated through PTH1R activation and downstream cAMP signaling.
• Phosphate excretion: PTH inhibits phosphate reabsorption in the proximal convoluted tubule by causing internalization of the type IIa and IIc sodium-phosphate co-transporters (NaPi-IIa and NaPi-IIc) from the apical membrane. This leads to increased urinary phosphate excretion (phosphaturia) and decreased serum phosphate levels. The phosphaturic effect of PTH is important because it prevents the calcium released from bone resorption from being “trapped” as insoluble calcium-phosphate complexes in the blood.
• Calcitriol production: As mentioned above, PTH stimulates renal 1-alpha-hydroxylase activity, increasing the conversion of 25(OH)D to calcitriol, which amplifies intestinal calcium absorption (Holick, 2007).

Actions on the Intestine (Indirect):

PTH does not act directly on intestinal cells to any significant degree. Instead, its intestinal effects are entirely mediated through calcitriol—PTH stimulates the kidneys to produce more calcitriol, which then travels to the small intestine and increases the expression of calcium transport proteins, dramatically enhancing dietary calcium absorption.

The Calcium-PTH Relationship: Understanding the Hormonal Axis

Graphing the Relationship Between Calcium and PTH

One of the most instructive ways to understand hyperparathyroidism is to visualize the mathematical and physiological relationship between serum calcium and parathyroid hormone on a graph. Imagine a two-dimensional plot where calcium is represented on the horizontal (X) axis and parathyroid hormone (PTH) is represented on the vertical (Y) axis. In a healthy individual, as calcium levels rise, PTH levels fall—and as calcium levels fall, PTH levels rise. This inverse, feedback-regulated relationship is what keeps serum calcium within its narrow physiological range of approximately 8.5 to 10.5 mg/dL (Insogna, 2018).

In primary hyperparathyroidism, this regulatory relationship is disrupted. When you plot the laboratory values of a patient with primary hyperparathyroidism, their data point falls in the upper right quadrant of the graph—meaning they have both a high calcium and a high PTH simultaneously. This co-elevation of both calcium and PTH is the pathognomonic laboratory signature of primary hyperparathyroidism. It reflects the fundamental pathophysiology of the condition: an abnormal parathyroid gland (most commonly an adenoma) that secretes PTH autonomously, without regard for the normal feedback suppression that should occur when calcium levels are elevated (Bilezikian et al., 2022).

By contrast, if a patient has hypercalcemia (elevated calcium) but a low or suppressed PTH, this clinical picture suggests a different etiology entirely. In this scenario—which falls in the lower right quadrant of our hypothetical graph—we should consider causes of hypercalcemia that are independent of PTH dysregulation. These include:

• Excess calcium intake: Patients who consume very large amounts of supplemental calcium, particularly in the context of low fluid intake, can develop milk-alkali syndrome and associated hypercalcemia.
• Excess vitamin D intake or toxicity: Supplemental vitamin D in supraphysiological doses can drive intestinal calcium absorption to the point of hypercalcemia.
• Hypercalcemia of malignancy: Many cancers can cause hypercalcemia through the secretion of PTH-related peptide (PTHrP), which mimics the actions of PTH on bone and kidney but is not detected by standard PTH assays. Solid tumors such as squamous cell carcinoma of the lung, renal cell carcinoma, and breast cancer are common culprits (Stewart, 2005). Hematologic malignancies such as multiple myeloma can cause hypercalcemia through direct osteolytic destruction of bone.
• Granulomatous diseases: Conditions such as sarcoidosis, tuberculosis, and histoplasmosis can cause hypercalcemia through the ectopic production of calcitriol (active vitamin D) by activated macrophages within granulomas (Kallas et al., 2010).

Understanding where a patient’s laboratory data falls on this calcium-PTH graph is the first and most critical step in narrowing the differential diagnosis of hypercalcemia and determining the most appropriate workup and management strategy.

Consequences of Too Little PTH: Hypoparathyroidism and Hypocalcemia

When the parathyroid glands produce insufficient PTH—a condition called hypoparathyroidism—the physiological mechanisms that maintain serum calcium are impaired, leading to hypocalcemia. The most common cause of hypoparathyroidism is inadvertent surgical damage or removal of the parathyroid glands during thyroid or parathyroid surgery. Less commonly, hypoparathyroidism can be autoimmune, genetic, or associated with hypomagnesemia (since adequate magnesium is required for PTH secretion and action) (Bilezikian et al., 2022).

The clinical manifestations of hypocalcemia reflect calcium’s role in neuromuscular function and membrane stability. They include:

• Perioral numbness and tingling (circumoral paresthesias)
• Carpopedal spasm (involuntary flexion of the wrists and ankles—the classic “main d’accoucheur” posture)
• Chvostek’s sign: Tapping over the facial nerve at the angle of the jaw produces involuntary facial muscle twitching
• Trousseau’s sign: Inflating a blood pressure cuff above systolic pressure for 3 minutes produces carpopedal spasm
• Laryngospasm (in severe cases)
• Seizures (in severe cases)
• Prolonged QT interval on ECG, increasing arrhythmia risk

Consequences of Too Much PTH: Hyperparathyroidism and Hypercalcemia

When the parathyroid glands produce excessive PTH—the defining feature of hyperparathyroidism—serum calcium rises above the normal range, producing the clinical syndrome of hypercalcemia. The symptoms of hypercalcemia are often described using the classic medical mnemonic “bones, stones, abdominal groans, and psychic moans”, which elegantly captures the four major organ systems affected:

• Bones: Bone pain, osteoporosis, pathological fractures, and (in severe, longstanding cases) osteitis fibrosa cysticlongstandingdney stones (nephrolithiasis), nephrocalcinosis, renal dysfunction
• Abdominal groans: Nausea, vomiting, constipation, anorexia, peptic ulcer disease, pancreatitis
• Psychic moans: Depression, anxiety, cognitive impairment, lethargy, confusion

The Clinical Spectrum of Hypercalcemia: From Asymptomatic to Life-Threatening

Understanding the Calcium Threshold for Symptoms

One of the most important clinical concepts in managing hypercalcemia is the recognition that symptoms are not linear with calcium levels. There is a threshold effect, and the relationship between calcium levels and symptom severity is influenced by the rate of rise as well as the absolute level.

In modern clinical practice, the majority of patients with primary hyperparathyroidism discovered through routine screening have mild hypercalcemia, typically with serum calcium levels in the range of 10.5 to 11.5 mg/dL. Many of these patients are entirely asymptomatic—they have no idea their calcium is elevated until a metabolic panel returns from a routine physical examination. This asymptomatic presentation is now so common that the 2022 Fourth International Workshop on the Management of Asymptomatic Primary Hyperparathyroidism specifically addresses the evaluation and management of this large group of patients (Bilezikian et al., 2022).

When calcium levels climb into the range of 11 to 12 mg/dL, patients may begin to experience mild but nonspecific symptoms. These often include:

• Polyuria (increased urination): High serum calcium impairs the kidney’s ability to concentrate urine by reducing the expression and function of aquaporin water channels in the collecting duct, producing a form of nephrogenic diabetes insipidus. Patients produce large volumes of dilute urine.
• Polydipsia (increased thirst): The polyuria driven by hypercalcemia leads to compensatory increases in fluid intake.
• Nocturia (waking at night to urinate): The osmotic diuresis from hypercalcemia does not cease during sleep, so patients with significant hypercalcemia are frequently awakened at night by the urge to urinate.

It is critically important to recognize that this triad of polyuria, polydipsia, and nocturia is clinically indistinguishable from the presentation of new-onset diabetes mellitus. In a busy outpatient practice, a patient presenting with these three symptoms will most commonly be tested for blood glucose and HbA1c—and if the clinician does not also check a serum calcium, an underlying hyperparathyroidism may be missed entirely. I have seen this scenario play out clinically, and it underscores the importance of including a complete metabolic panel (which includes calcium) in the workup of any patient presenting with polyuria and polydipsia.

As calcium levels rise further—typically into the range of 11 to 12+ mg/dL—symptoms become more prominent and affect the gastrointestinal system:

• Nausea and vomiting: Hypercalcemia reduces the contractility of smooth muscle in the gastrointestinal tract, slowing gastric emptying and producing nausea and vomiting.
• Constipation: Reduced colonic motility secondary to hypercalcemia leads to constipation, which can range from mild to severe.
• Anorexia: Loss of appetite is common and contributes to the malnutrition and weight loss seen in chronic hypercalcemia.
• Abdominal pain: In some patients, hypercalcemia can trigger acute pancreatitis—a potentially life-threatening emergency—through mechanisms that are not entirely understood but may involve calcium-mediated activation of pancreatic enzymes within acinar cells.

Neurological and psychiatric symptoms are among the most diagnostically challenging manifestations of hypercalcemia because they are so nonspecific and can be attributed to many other conditions. They include:

• Cognitive impairment and difficulty concentrating
• Depression and anxiety
• Fatigue and weakness
• Lethargy progressing to confusion

At calcium levels above 12 to 14 mg/dL, particularly when the elevation is acute rather than longstanding, patients can develop:

• Prolonged and altered mental status: Hypercalcemia impairs neuronal transmission and can produce a clinical picture resembling delirium or dementia.
• Obtundation or coma: In severe hypercalcemia, the central nervous system depressant effects can progress to frank obtundation or loss of consciousness.
• Acute kidney injury: The combination of severe polyuria (leading to volume depletion), direct renal tubular toxicity from hypercalcemia, and nephrocalcinosis can produce acute kidney injury (AKI). This creates a vicious cycle: volume depletion reduces glomerular filtration rate, which impairs renal calcium excretion, which further raises serum calcium.
• Hypercalcemic crisis: The most severe presentation of hypercalcemia, characterized by calcium levels typically above 14 mg/dL, severe dehydration, renal failure, altered consciousness, and potentially fatal cardiac arrhythmias. This constitutes a medical emergency requiring urgent hospitalization and intravenous fluid resuscitation.

Differentiating Symptomatic Thresholds in Clinical Practice

In my clinical practice alongside Dr. Cardenas, we have developed a systematic approach to evaluating patients with hypercalcemia that considers both the absolute calcium level and the clinical context:

• Calcium 10.5-11.0 mg/dL: Most patients in this range are asymptomatic. We pursue a thorough workup (PTH, vitamin D levels, 24-hour urine calcium) but typically do not initiate urgent intervention. This is the range where careful monitoring and patient education are paramount.
• Calcium 11.0-12.0 mg/dL: Patients may have subtle symptoms (fatigue, mild polyuria, constipation). We intensify the workup and begin considering surgical referral if PTH is elevated (consistent with primary hyperparathyroidism) and the patient meets criteria for intervention.
• Calcium 12.0-14.0 mg/dL: Patients are typically symptomatic. Prompt evaluation and intervention are indicated. If the patient can be managed outpatient, close follow-up is essential. If the patient has significant symptoms or concurrent illness, hospitalization may be warranted.
• Calcium > 14.0 mg/dL: This represents a potential endocrine emergency. We coordinate urgent hospitalization, intravenous hydration, bisphosphonate therapy (for hypercalcemia of malignancy), and specialist consultation.

“Cracking the Low Thyroid Code: A Comprehensive Assessment Guide”- Video

Primary Hyperparathyroidism: To Treat or to Watch?

One of the most challenging aspects of managing primary hyperparathyroidism is communicating the diagnosis and treatment options to patients. Often, the condition is discovered incidentally on a routine lab test, and the patient may feel perfectly fine, exhibiting no symptoms at all. Imagine being told you have a condition that might require neck surgery, yet you feel completely healthy. This is a common scenario, and it’s where careful, evidence-based education becomes paramount.

A Landmark Study on Quality of Life

To help patients navigate this decision, I frequently refer to a pivotal study by Pretorius et al. (2020) that sheds light on the long-term outcomes of surgery versus observation. I find this research particularly valuable because it directly addresses the patient’s primary concern: “Will this surgery actually make me feel better?”

The study, titled “Effect of parathyroidectomy on quality of life in asymptomatic primary hyperparathyroidism: a 10-year follow-up of a randomized controlled trial”, provides some of the most robust data we have on this topic. Here’s a breakdown of its design and findings:

• Study Population: The researchers enrolled 191 patients who were diagnosed with asymptomatic primary hyperparathyroidism. This is the key group we are often dealing with in clinical practice.
• Methodology: The patients were randomized in a one-to-one ratio into two groups:

1. 1. Surgery Group: This group underwent a parathyroidectomy, the surgical removal of the overactive parathyroid gland(s).
   2. Observation Group: This group was monitored over time without surgical intervention.

• Outcome Measures: The researchers used two validated quality-of-life questionnaires: the Short Form 36 (SF-36) and the Comprehensive Psychopathological Rating Scale (CPRS). These scales were administered at the beginning of the study (baseline) and then at 2, 5, and 10 years.
• Biochemical Results: As expected, the surgical group achieved a biochemical cure. Their calcium and parathyroid hormone (PTH) levels returned to normal after the procedure. In contrast, the observation group’s calcium and PTH levels remained elevated throughout the ten years.

The Surprising Conclusion

Now, here is the part that often surprises both clinicians and patients. When the researchers analyzed the quality-of-life data after ten years, the results were not as clear-cut as one might assume.

• On the SF-36 scale, which measures eight different domains of health (like physical functioning, pain, and emotional well-being), only one domain—vitality—showed a significant improvement in the surgery group compared to the observation group.
• On the CPRS scale, which assesses a wide range of psychiatric and somatic symptoms, both groups improved similarly over the decade.

The ultimate conclusion of this ten-year, prospective, randomized controlled trial was profound: parathyroid surgery does not necessarily lead to a major improvement in overall quality of life for asymptomatic patients, and conversely, observation does not lead to a worsening of quality of life.

I make it a point to sit with my patients and let this information sink in. It empowers them by showing that “watching and waiting” is a valid, evidence-based strategy. It shifts the conversation from a rushed decision to a thoughtful, collaborative process. Of course, this is only true as long as the patient does not develop clear indications for surgery, which we will discuss in detail later. But having the space and time to monitor the condition is often the best initial course of action.

Primary Hyperparathyroidism: Pathophysiology, Epidemiology, and Etiology

Defining Primary Hyperparathyroidism

Primary hyperparathyroidism (PHPT) is defined as the autonomous, excessive secretion of parathyroid hormone (PTH) by one or more abnormal parathyroid glands, leading to hypercalcemia. The term “primary” distinguishes this condition from secondary hyperparathyroidism, in which PTH hypersecretion is a physiological response to persistent hypocalcemia (as occurs in chronic kidney disease or vitamin D deficiency), and tertiary hyperparathyroidism, in which longstanding secondary hyperparathyroidism longstandingonomous PTH secretion that persists even after the underlying cause of hypocalcemia is corrected (as may occur after kidney transplantation in patients who had severe secondary hyperparathyroidism before transplant) (Bilezikian et al., 2022).

In primary hyperparathyroidism, the problem originates within the parathyroid glands themselves—the glands have lost their normal responsiveness to the suppressive effects of elevated calcium on PTH secretion. Instead of reducing PTH output when calcium rises, the abnormal parathyroid tissue continues to secrete PTH at inappropriately high levels, maintaining and worsening the hypercalcemia in a self-perpetuating cycle.

Epidemiology of Primary Hyperparathyroidism: A Tale of Two Cities

The clinical presentation of primary hyperparathyroidism is not uniform across the globe. It is a fascinating example of how genetics, environment, and healthcare systems can shape the manifestation of a single disease. A study published in 2000 by Bilezikian et al., which I often refer to as “The Tale of Two Cities,” beautifully illustrates this dichotomy by comparing patients in the United States with patients in Beijing, China.

PHPT is the third most common endocrine disorder in the general population, after diabetes mellitus and thyroid disease (Insogna, 2018). It affects approximately 1 in 500 to 1 in 1,000 adults in the United States, with an estimated 100,000 new cases diagnosed annually. The condition has a strong female predominance, with women affected approximately 3 to 4 times more frequently than men, particularly in the postmenopausal age group (typically diagnosed in the 6th and 7th decades of life, though the condition can occur at any age) (Bilezikian et al., 2022).

The Presentation in the United States

In developed nations like the U.S., the widespread use of automated, multi-channel blood chemistry panels has fundamentally changed how we encounter hyperparathyroidism. Here’s what the typical presentation looks like based on the 100 subjects studied from the United States:

• Asymptomatic Hypercalcemia: The disease is most commonly identified as an incidental finding of high calcium on a routine blood test.
• Demographics: It typically affects individuals about ten years after menopause.
• Laboratory Profile:

• • Average Serum Calcium: 10.4 mg/dL (mildly elevated).
  • Average PTH: 118 pg/mL (moderately elevated).
  • Average Vitamin D (25-hydroxyvitamin D): 21 ng/mL (often insufficient).

• Bone Disease: Overt radiological evidence of bone disease, like the classic osteitis fibrosa cystica (characterized by “brown tumors” and bone cysts), is now extremely rare. Skeletal involvement is usually only detected through the subtle changes measured by bone densitometry (DEXA scan), revealing osteopenia or osteoporosis.
• Kidney Stones: The incidence of kidney stone disease (nephrolithiasis) has dramatically decreased. While it was as high as 60% in the 1940s, current estimates place it between 15% and 20% in this patient population.

The Presentation in Beijing, China

The picture in Beijing, at the time of the study, was starkly different, reflecting a more classic and severe form of the disease. Here’s the profile of the 100 subjects from China:

• Symptomatic and Severe: The disease was far from asymptomatic. Patients presented with significant clinical manifestations.
• Demographics: The average age of onset was much younger, at 37 years.
• Laboratory Profile:

• • Average Serum Calcium: 12.0 mg/dL (significantly higher).
  • Average PTH: Values were often over 20 times the upper limit of normal, indicating profoundly overactive glands.
  • Average Vitamin D: A striking 8 ng/mL, indicating severe deficiency. This is a critical factor, as profound vitamin D deficiency can exacerbate hyperparathyroidism.

• Bone Disease: The consequences were devastating.

• • Radiological evidence of osteitis fibrosa cystica was present in 60% of patients.
  • Pathological fractures (fractures occurring with minimal or no trauma) were seen in 35% of patients, typically affecting the femur or humerus.
  • Nearly all patients had osteoporosis.

• Kidney Stones: 42% of patients demonstrated kidney stones.
• Constitutional Symptoms: Profound weakness and fatigue were almost universally present.

In El Paso, Texas—a predominantly Hispanic community—I see patterns consistent with national epidemiological data. However, vitamin D insufficiency is highly prevalent in our patient population due to factors including dietary patterns, limited sun exposure among indoor workers, and the high prevalence of chronic conditions associated with vitamin D deficiency (such as obesity and diabetes). This vitamin D insufficiency context is clinically important because coexisting vitamin D deficiency can mask the full severity of primary hyperparathyroidism and must be identified and addressed as part of the comprehensive evaluation.

Causes of Primary Hyperparathyroidism

Solitary parathyroid adenoma is by far the most common cause of PHPT, accounting for approximately 80 to 85% of cases. An adenoma is a benign, monoclonal neoplasm of parathyroid chief cells. This single gland has undergone somatic mutation(s) leading to unregulated autonomous proliferation and PTH secretion, while the remaining three glands are normal (or even suppressed due to the hypercalcemia). Adenomas typically weigh between 0.5 and several grams (compared to the normal 30-40 mg per gland) and are encapsulated. On imaging (ultrasound, sestamibi scan), they typically appear as a discrete, well-defined ovoid lesion posterior to or within the thyroid gland (Delellis et al., 2022).

Multi-gland hyperplasia (also called four-gland hyperplasia) accounts for approximately 10 to 15% of cases, and involves enlargement and hypersecretion of all four parathyroid glands. This pattern is more common in the setting of multiple endocrine neoplasia (MEN) syndromes—particularly MEN type 1 (associated with mutations in the MEN1 gene encoding menin) and MEN type 2A (associated with RET proto-oncogene mutations)—as well as in the rare condition of familial hyperparathyroidism unrelated to MEN. Management of multi-gland hyperplasia is more surgically complex than adenoma resection, typically requiring removal of 3.5 glands (subtotal parathyroidectomy) or all four glands with autotransplantation of parathyroid tissue to the forearm (Bilezikian et al., 2022).

Double adenomas (two adenomas affecting two separate glands, while the other two glands are normal) are less common, accounting for approximately 2 to 5% of cases. They can be challenging to distinguish from multi-gland hyperplasia on preoperative imaging.

Parathyroid carcinoma is rare, accounting for less than 1% of PHPT cases, but is clinically important because it is associated with more severe hypercalcemia, a higher recurrence rate after surgery, and a more guarded prognosis. Clinical features that raise suspicion for carcinoma include very high calcium and PTH levels (often > 14 mg/dL and > 500 pg/mL, respectively), a palpable neck mass, concurrent skeletal and renal manifestations, and local invasion on imaging (Delellis et al., 2022).

Diagnostic Workup of Hyperparathyroidism: Laboratory and Radiological Evaluation

The diagnostic workup of suspected or confirmed hyperparathyroidism requires a systematic approach that establishes the diagnosis, assesses the severity, evaluates for complications, and rules out other causes of hypercalcemia. In my practice, I work closely with Dr. Cardenas to ensure each patient receives a comprehensive, evidence-based evaluation. When you encounter a patient with elevated calcium, the most practical way to structure your thinking and your workup is to consider the indications for surgery. This framework will naturally guide you to order the necessary tests.

Initial Laboratory Evaluation

Essential initial laboratory tests:

• Serum calcium (total and/or ionized): Establishes the presence and degree of hypercalcemia. Repeat measurements on at least two separate occasions are recommended to confirm persistent hypercalcemia before diagnosing PHPT (Bilezikian et al., 2022).
• Serum albumin: Required to calculate corrected calcium in patients with abnormal albumin levels.
• Intact PTH (iPTH): The simultaneous measurement of PTH in the context of hypercalcemia is the single most important test in the workup of PHPT. A PTH level that is elevated (or even in the upper half of the normal range, which is “inappropriately normal” in the context of hypercalcemia) establishes the diagnosis of primary or tertiary hyperparathyroidism. A suppressed PTH in the context of hypercalcemia points toward non-PTH-mediated causes (malignancy, excess vitamin D, granulomatous disease, etc.).
• Serum phosphate: Typically low or low-normal in PHPT due to PTH’s phosphaturic effect on the kidney. Hypophosphatemia supports the diagnosis and also contributes to the metabolic bone disease seen in PHPT.
• Serum 25-hydroxyvitamin D: Vitamin D status must be assessed in all patients with PHPT. Coexisting vitamin D deficiency can mask the severity of hypercalcemia (because vitamin D deficiency impairs intestinal calcium absorption), and it is associated with larger parathyroid adenomas, higher PTH levels, and more severe bone disease. Correcting vitamin D deficiency before or after surgical intervention improves outcomes (Bilezikian et al., 2022).
• Serum creatinine and eGFR: Renal function must be assessed because hypercalcemia can cause nephrotoxicity, and because impaired renal function (CKD) can itself cause secondary hyperparathyroidism.
• 24-hour urine calcium and creatinine: This is a critically important test that serves two purposes. First, it assesses the degree of hypercalciuria (excess urinary calcium excretion), which is a risk factor for kidney stones and an indication for surgery in asymptomatic PHPT. Second, and very importantly, it helps distinguish PHPT from familial hypocalciuric hypercalcemia (FHH)—a benign, autosomal dominant condition caused by a loss-of-function mutation in the CaSR gene that produces hypercalcemia with a very low urinary calcium excretion. In FHH, surgery is not beneficial and is specifically contraindicated. The calcium-to-creatinine clearance ratio (CCCR)—calculated as (urine calcium/serum calcium) / (urine creatinine/serum creatinine)—is used to differentiate FHH (CCCR < 0.01) from PHPT (CCCR typically > 0.02) (Bilezikian et al., 2022).
• Serum alkaline phosphatase and bone-specific alkaline phosphatase: Elevated in patients with significant bone turnover, reflecting osteoblastic activity in response to PTH-driven bone resorption.
• PTHrP (PTH-related peptide): Checked if malignancy-associated hypercalcemia is suspected.
• 1,25-dihydroxyvitamin D (calcitriol): Elevated in granulomatous diseases (sarcoidosis, TB) due to ectopic production by activated macrophages; may also be elevated in PHPT.
• Serum and urine protein electrophoresis (SPEP/UPEP): If multiple myeloma is a concern.
• Thyroid function tests (TSH): Hyperthyroidism can contribute to hypercalcemia through increased bone turnover.

Additional considerations for genetic testing:

In patients with PHPT diagnosed at a young age (< 40 years), multi-gland disease, recurrent PHPT, or a family history of hypercalcemia or endocrine tumors, genetic testing for mutations in MEN1, MEN2A (RET), CDC73 (hyperparathyroidism-jaw tumor syndrome), and CaSR should be considered to identify hereditary syndromes that require different management and family screening (Bilezikian et al., 2022).

Radiological and Imaging Evaluation

Imaging in PHPT serves primarily preoperative purposes—it is used to localize the abnormal parathyroid gland(s) before surgery, enabling the surgeon to plan a minimally invasive approach. Importantly, imaging results do not establish or confirm the diagnosis of PHPT, which is a biochemical diagnosis based on the combination of hypercalcemia and elevated (or inappropriately normal) PTH. A normal or negative imaging study does not rule out PHPT, and surgery should not be withheld from a patient who meets biochemical and clinical criteria for surgery simply because preoperative localization studies are negative.

Neck Ultrasound:

Neck ultrasound is non-invasive, inexpensive, and widely available, and it is typically the first imaging modality used in the preoperative evaluation of PHPT. It has a sensitivity of approximately 70-80% for detecting solitary parathyroid adenomas and is particularly useful for identifying glands that are in typical anatomical locations adjacent to the thyroid (Delellis et al., 2022). Ultrasound can also detect concurrent thyroid pathology (nodules, goiter) that may need to be addressed at the time of parathyroid surgery. However, ultrasound is operator-dependent and has limited sensitivity for ectopic glands.

Sestamibi Scintigraphy (Parathyroid Scan):

Technetium-99m sestamibi (MIBI) scintigraphy is a nuclear medicine imaging technique that exploits the fact that abnormal, hyperfunctioning parathyroid tissue retains sestamibi for longer than normal thyroid and parathyroid tissue. When combined with SPECT (single-photon emission computed tomography) imaging, sestamibi scanning provides three-dimensional localization of abnormal parathyroid glands. It has a sensitivity of approximately 80-90% for solitary adenomas (Delellis et al., 2022). The combination of concordant ultrasound and sestamibi results has a very high positive predictive value (> 95%) and is the standard basis for planning a minimally invasive parathyroidectomy (MIP).

Four-Dimensional CT (4D-CT):

4D-CT combines standard computed tomography with contrast enhancement at multiple time phases, exploiting the characteristic vascular blush pattern of hyperfunctioning parathyroid tissue. It has sensitivity comparable to or better than sestamibi-SPECT for localizing parathyroid adenomas. It provides superior anatomical detail, which is particularly valuable in patients with ectopic glands or in the setting of re-operative parathyroid surgery (Delellis et al., 2022). Its primary limitation is radiation exposure and the requirement for intravenous contrast.

MRI:

MRI of the neck and mediastinum may be used in patients in whom other imaging modalities have failed to localize the abnormal gland, and in patients with contrast allergy or concerns about radiation exposure. It offers excellent soft tissue contrast and is particularly useful for identifying ectopic mediastinal parathyroid adenomas (Delellis et al., 2022).

PET-CT with C-11 Methionine or F-18 Fluorocholine:

Emerging nuclear medicine techniques using C-11 methionine PET or F-18 fluorocholine PET have shown very high sensitivity and specificity for parathyroid adenoma localization, even in cases where conventional imaging has been negative. These techniques are increasingly available at major academic centers and represent a significant advance for patients with persistent or recurrent PHPT who need re-operative surgery (Delellis et al., 2022).

Bone Density Measurement (DXA):

Dual-energy X-ray absorptiometry (DXA) is used to assess bone mineral density (BMD) in patients with PHPT. This is important because PTH-driven bone resorption preferentially affects cortical bone (such as the distal one-third of the radius). DXA results at the three standard sites (lumbar spine, hip, and distal radius) provide important prognostic information. They are used in the criteria for surgical intervention in asymptomatic PHPT (Bilezikian et al., 2022).

Renal Imaging:

Because kidney stones are a significant complication of PHPT, renal ultrasound or CT of the kidneys should be performed in all patients with PHPT to detect nephrolithiasis or nephrocalcinosis that may not be clinically apparent. The presence of asymptomatic kidney stones on imaging is now recognized as an indication for surgery in patients with PHPT who might otherwise be considered asymptomatic (Bilezikian et al., 2022).

Surgical Management of Primary Hyperparathyroidism: Parathyroidectomy

Indications for Surgery

Parathyroidectomy—surgical removal of the abnormal parathyroid gland(s)—is the only curative treatment for primary hyperparathyroidism and is the management of choice for virtually all patients with symptomatic PHPT and for many patients with asymptomatic PHPT who meet specific criteria.

The 2022 guidelines from the Fourth International Workshop on Asymptomatic Primary Hyperparathyroidism (Bilezikian et al., 2022) recommend parathyroidectomy for patients with PHPT who have any of the following:

• Age: Less than 50 years old.
• Serum Calcium: A level that is 1.0 mg/dL or more above the upper limit of the normal range for the specific lab performing the test.
• Kidney Involvement:

• • A history of kidney stones or evidence of stones on imaging (nephrolithiasis).
  • A Glomerular Filtration Rate (eGFR) of less than 60 mL/min/1.73m².

• Skeletal Involvement:

• • A diagnosis of osteoporosis on a DEXA scan (T-score of -2.5 or lower at the lumbar spine, hip, or distal radius).
  • A history of a vertebral fragility fracture.

• Urinary Calcium:

• • A 24-hour urine calcium excretion of >400 mg/day.

For patients who do not meet these criteria and choose not to undergo surgery, medical monitoring with regular follow-up is an acceptable alternative.

Surgical Technique: Minimally Invasive vs. Traditional Bilateral Exploration

Minimally invasive parathyroidectomy (MIP) has become the surgical procedure of choice at most experienced centers for patients with concordant preoperative imaging demonstrating a solitary adenoma. This approach involves a small (2-3 cm) incision focused directly on the localized gland, with intraoperative confirmation of cure using rapid intraoperative PTH (ioPTH) monitoring.

The Miami criterion for ioPTH adequacy specifies that PTH levels should fall by > 50% from the highest preoperative value within 10 minutes of gland removal, confirming that all hyperfunctioning tissue has been removed and that a cure has been achieved. The intraoperative PTH assay has revolutionized parathyroid surgery by providing real-time biochemical confirmation of cure, dramatically reducing the rate of persistent or recurrent hyperparathyroidism (Bilezikian et al., 2022).

Bilateral neck exploration (BNE) remains the procedure of choice for patients in whom preoperative imaging is discordant, negative, or in whom multi-gland disease is suspected (as in MEN syndromes). BNE involves systematic examination of all four parathyroid glands through a transverse neck incision, with removal of all abnormal-appearing glands.

Complications of Parathyroid Surgery

While parathyroid surgery is generally safe and well-tolerated, it is not without potential complications:

• Hypocalcemia (hungry bone syndrome): After removal of the hyperfunctioning parathyroid gland(s), the abrupt fall in PTH levels unmasks the calcium deficit in bones that had been chronically resorbed. Calcium is rapidly deposited back into bone, leading to symptomatic hypocalcemia requiring calcium and vitamin D supplementation (Bilezikian et al., 2022).
• Hypoparathyroidism: Temporary or permanent impairment of the remaining parathyroid glands due to surgical manipulation, devascularization, or inadvertent removal.
• Recurrent laryngeal nerve injury: Injury to the nerve that controls the vocal cords can result in hoarseness or, rarely, airway compromise. The risk of permanent injury is ~1%.
• Hematoma: Postoperative bleeding in the neck can compress the airway and represents a surgical emergency, though this is rare (1 in 300 risk).
• Recurrent or Persistent Disease: In 4-5% of cases, hyperparathyroidism may persist or recur after surgery, often due to an undiscovered second adenoma or underlying multi-gland disease.

Medical Management of Primary Hyperparathyroidism

When Medical Management Is Appropriate

For patients with PHPT who do not meet surgical criteria or who decline surgery, or who have significant medical comorbidities that make surgery high-risk, medical management with close surveillance is a reasonable approach. The goals of medical management are to control symptoms, prevent disease progression, maintain bone density, and prevent kidney stone formation.

Surveillance Protocol for Asymptomatic PHPT

For patients managed medically, the following surveillance schedule is recommended (Bilezikian et al., 2022):

• Annual serum calcium and PTH
• Annual serum creatinine and eGFR
• DXA bone density every 1-2 years (all three sites: lumbar spine, hip, and distal radius)
• Renal imaging every 1-2 years (ultrasound or CT KUB to screen for new stones)
• Annual 24-hour urine calcium and creatinine
• Annual 25-hydroxyvitamin D (correcting deficiency as needed)

Pharmacological Options

1. Bisphosphonates (Alendronate, Zoledronic acid):

Bisphosphonates are potent inhibitors of osteoclast-mediated bone resorption and have been shown to increase bone mineral density at the lumbar spine and hip in patients with PHPT who cannot or choose not to undergo surgery. However, bisphosphonates do not significantly reduce PTH levels or serum calcium in most patients with PHPT, meaning they address one complication (bone loss) without treating the underlying hormonal abnormality (Khan et al., 2004).

2. Selective Estrogen Receptor Modulators (Raloxifene):

In postmenopausal women with PHPT who cannot undergo surgery, raloxifene can modestly reduce serum calcium and improve bone density through estrogen-receptor-mediated inhibition of bone resorption. It is generally less potent than bisphosphonates but may be preferred in some patients (Rubin et al., 2008).

3. Cinacalcet (Calcimimetic):

Cinacalcet (Sensipar) is the most targeted pharmacological treatment available for PHPT. As a calcimimetic agent, it acts as a positive allosteric modulator of the calcium-sensing receptor (CaSR) on parathyroid chief cells, making the CaSR more sensitive to ambient calcium levels and thereby reducing PTH secretion and lowering serum calcium. Cinacalcet reliably normalizes serum calcium in the majority of patients with PHPT who take it, making it particularly valuable for patients in whom hypercalcemia itself is the primary management concern (Peacock et al., 2011). However, it does not consistently increase bone mineral density and is most appropriate for patients in whom controlling hypercalcemia is the primary goal.

4. Vitamin D Supplementation:

The evidence indicates that cautious correction of vitamin D deficiency in patients with PHPT is safe and is associated with a reduction in PTH levels without a significant increase in serum calcium (Bilezikian et al., 2022). The general approach is to correct vitamin D deficiency to a 25(OH)D level of at least 20-30 ng/mL with careful monitoring of serum and urine calcium.

5. Hydration and Calcium Restriction:

Patients with PHPT and hypercalciuria are advised to maintain adequate hydration (at least 2 liters of fluid per day) to reduce the risk of kidney stones. Moderate dietary calcium restriction is sometimes recommended, though extreme restriction can paradoxically worsen bone loss (Bilezikian et al., 2022).

Clinical Case Studies from Our Practice

Theoretical knowledge provides the foundation, but the real learning happens in the clinic. I want to share three case studies from my practice that highlight the diverse challenges we encounter when managing primary hyperparathyroidism.

Case Study 1: The Cardiac Patient with Surprising Relief

A 68-year-old Caucasian male with a significant history of cardiovascular disease (non-ischemic cardiomyopathy, chronic heart failure, atrial fibrillation) was referred to our clinic by his cardiologist for a parathyroid hormone (PTH) level of 190 pg/mL. His primary complaint was vague muscle achiness, but it would have been easy to attribute any fatigue to his heart condition.

His initial labs with us confirmed primary hyperparathyroidism:

• Calcium: 10.8 mg/dL (elevated)
• Intact PTH: 158 pg/mL (elevated)
• Vitamin D (25-OH):3 ng/mL (insufficient)
• Glomerular Filtration Rate (GFR):4 mL/min (mildly decreased)
• 24-Hour Urine Calcium: 364 mg/24 hours (elevated)

He met multiple criteria for surgery. A neck ultrasound was key, identifying a nodule highly suspicious for a parathyroid adenoma posterior to the left thyroid lobe. I referred him to an endocrine surgeon, and in April of 2024, he underwent a successful parathyroidectomy. Intraoperative PTH monitoring showed a dramatic drop from a baseline of 533 pg/mL to 42 pg/mL just 15 minutes after removal, confirming a cure.

When I saw him for follow-up, he told me he “felt better immediately after surgery,” with a significant improvement in energy that allowed him to play golf again. This was a powerful lesson: his profound fatigue, which everyone had attributed to his heart disease, was largely driven by his hyperparathyroidism. It highlights the non-specific but debilitating “constitutional” symptoms that can accompany this condition.

Case Study 2: The Nonspecifics of Medical Management

This next case involves an 85-year-old Caucasian female with chronic dementia whose journey began with an emergency room visit for weakness and confusion, where her calcium was a life-threatening 15.8 mg/dL. After aggressive treatment and a workup that ruled out malignancy, her family opted for medical management due to her age and comorbidities.

The following timeline shows the challenge we faced, where Dr. Cardenas’s internal medicine expertise was critical:

• October 2024 (Post-hospital): Calcium was 10.3 mg/dL, a great improvement.
• December 2024: Calcium rose to 11.4 mg/dL.
• January 2025: Calcium climbed to 11.8 mg/dL. We initiated cinacalcet at 30 mg daily.
• Post-Cinacalcet: She required another hospitalization with a calcium of 8 mg/dL. We increased her cinacalcet to 30 mg twice a day.
• Weeks Later: Calcium was still rising (12.2 mg/dL). We increased her dose to 60 mg twice a day.
• April 2025: Calcium reached 12.7 mg/dL. We had to increase her dose to the maximum dose of 90 mg twice a day.

Since then, she has required periodic infusions of zoledronic acid to control her calcium. This case taught me that clinical appearance can be deceiving; this pleasant, alert woman was walking around with some of the highest calcium levels I have ever seen. It also showed that medical management is a valid but demanding option that requires vigilant monitoring and a strong emphasis on hydration.

Case Study 3: The Pilot with Foot Pain

Our final case is a 57-year-old male pilot who was referred for an elevated calcium of 10.5 mg/dL and a PTH of 111 pg/mL. His most significant complaint was severe, bilateral foot pain that had plagued him for years.

His initial labs confirmed the diagnosis:

• Calcium: 11.5 mg/dL
• Intact PTH: 107 pg/mL
• Vitamin D: 43.2 ng/mL (excellent)

His neck ultrasound was initially inconclusive, but a renal ultrasound revealed a crucial, unexpected finding: a non-obstructing stone on the left kidney. He had no idea it was there. This asymptomatic nephrolithiasis provided a clear indication for surgery.

He underwent surgery in May of this year. When I saw him for his follow-up, the first thing he wanted to talk about was his feet. He was emphatic that the chronic, debilitating foot pain was so much better. This is another example of a non-specific “achiness” resolving dramatically after surgery. From a chiropractic perspective, it’s fascinating that a nonspecific systemic metabolic disorder was manifesting as localized musculoskeletal pain. Now that the metabolic driver is corrected, we can use chiropractic and rehabilitative therapies to address any residual biomechanical issues.

The Integrative Approach: Chiropractic Care, Internal Medicine, and Functional Medicine

At Injury Medical Clinic PA, we have built a clinical practice that represents the future of comprehensive care for complex conditions like hyperparathyroidism.

How Integrative Chiropractic Care Fits Into Hyperparathyroidism Management

It might initially seem that chiropractic care has a limited role in managing a hormonal disorder. This is a misconception I am committed to dispelling. Primary hyperparathyroidism produces profound effects on the musculoskeletal system that are directly within the scope of chiropractic expertise.

1. Osteoporosis and Bone Loss:

Elevated PTH drives osteoclast-mediated bone resorption, leading to decreased bone density and increased fracture risk. In my practice, I apply my training in functional and integrative medicine to develop individualized bone health protocols that incorporate:

• Weight-bearing and resistance exercise programs: Exercise is the most powerful non-pharmacological intervention for improving bone density. I provide individualized exercise prescriptions based on each patient’s bone density data and functional capacity (Beck et al., 2017).
• Spinal assessment and gentle manipulation/mobilization: Patients with PHPT-related osteoporosis require special consideration. Traditional high-velocity manipulation may be contraindicated, so I use modified low-force mobilization techniques and soft tissue therapies that are safe in the context of reduced bone density (Whedon & Mackenzie, 2018).
• Posture correction and spinal stabilization: Vertebral compression fractures produce characteristic kyphotic posturing. Targeted postural correction exercises, spinal stabilization training, and ergonomic education are central components of my chiropractic care.

2. Muscle Weakness and Fatigue:

Proximal muscle weakness is a recognized manifestation of chronic hypercalcemia. Therapeutic exercise, functional movement training, and neuromuscular rehabilitation are effective interventions for addressing this myopathy, and these are core competencies of chiropractic rehabilitation practice (Bilezikian et al., 2022).

3. Joint Pain and Soft Tissue Manifestations:

Hyperparathyroidism is associated with chondrocalcinosis (calcium crystal deposition in joint cartilage) and pseudogout, which can produce joint pain that may be the presenting complaint. Recognizing these musculoskeletal manifestations as potential markers of underlying metabolic disease is an example of the “gateway” role that chiropractors can play in identifying systemic conditions.

4. Postoperative Rehabilitation:

Following parathyroidectomy, patients may experience neck pain and stiffness. Chiropractic rehabilitation services—including gentle cervical mobilization, soft tissue therapy, and therapeutic exercise—facilitate recovery and improve functional outcomes after surgery (Whedon & Mackenzie, 2018).

Functional Medicine: Addressing Root Causes and Associated Factors

My certification in Functional Medicine (CFMP, IFMCP) enables me to take a systems-biology approach that goes beyond the conventional model. I assess:

Vitamin D Optimization: As discussed, vitamin D deficiency is highly prevalent in patients with PHPT. My approach integrates comprehensive vitamin D assessment with individualized supplementation protocols that aim to achieve optimal vitamin D status (typically 40-60 ng/mL) while carefully monitoring calcium (Holick et al., 2011).

Magnesium Status: Magnesium is a critical cofactor in PTH secretion and action. Many patients with PHPT are magnesium-deficient due to chronic polyuria. I routinely assess and replete magnesium as part of my functional medicine approach (Quitterer et al., 1997).

Inflammation and Immune Function: Emerging research suggests that chronic low-grade inflammation plays a role in parathyroid adenoma development. Addressing systemic inflammation through an anti-inflammatory diet, stress management, and targeted supplementation is a key component of my functional medicine approach.

Gut Health and Calcium Absorption: Because calcitriol-driven intestinal calcium absorption is a central mechanism in the hypercalcemia of PHPT, optimizing gut health is clinically relevant. Conditions like celiac disease or inflammatory bowel disease can create a compensatory rise in PTH that may complicate the evaluation of primary disease.

Personal Injury Care and Trauma-Related Musculoskeletal Conditions

At Injury Medical Clinic PA, we also serve many patients who have sustained personal injuries. A patient with undiagnosed PHPT and subclinical osteoporosis who sustains what appears to be a minor fall may actually suffer a pathological fracture. Recognizing this elevated fracture risk in the context of personal injury evaluation requires the kind of comprehensive, metabolically informed assessment that our integrative team is uniquely positioned to provide.

Other Forms and Special Considerations in Hyperparathyroidism

Secondary and Tertiary Hyperparathyroidism: The Kidney Disease Connection

While this post focuses on primary hyperparathyroidism, it’s crucial to understand other forms. Secondary hyperparathyroidism (SHPT) is a prevalent metabolic complication of chronic kidney disease (CKD). In CKD, the kidneys fail to activate vitamin D and excrete phosphate. The resulting hypocalcemia and hyperphosphatemia provide persistent stimulation to the parathyroid glands, causing them to secrete large amounts of PTH as a compensatory response (Ketteler et al., 2018).

Tertiary hyperparathyroidism develops when longstanding SHPT leads to autonomous secretion by the parathyroid glands. After a successful kidney transplant, these glands continue to secrete PTH at high levels, producing persistent hypercalcemia (Ketteler et al., 2018).

Normocalcemic Primary Hyperparathyroidism and the Gray Zone

A relatively recently recognized variant is normocalcemic primary hyperparathyroidism (NPHPT). In this condition, patients have chronically elevated PTH levels with consistently normal calcium, after all secondary causes (like vitamin D deficiency or CKD) have been excluded (Bilezikian et al., 2022). NPHPT is thought to represent an early or mild form of PHPT. The diagnostic challenge is the exhaustive exclusion of all secondary causes. In my practice in El Paso, where vitamin D insufficiency is prevalent, I always ensure a patient’s vitamin D is fully repleted before diagnosing NPHPT.

The Neuroendocrine and Neurological Manifestations

The neuropsychiatric manifestations of chronic hypercalcemia are among the most frequently overlooked aspects of PHPT. Symptoms like mild cognitive impairment, depression, fatigue, and anxiety are often attributed to other causes. Multiple studies have documented significant improvement in quality of life, mood, and cognitive function following successful parathyroidectomy, even in patients previously considered “asymptomatic” (Bilezikian et al., 2022). This evidence has been instrumental in broadening the criteria for surgical intervention.

The Calcium-Vitamin D-PTH Axis in Special Populations

• Pregnancy: Hyperparathyroidism during pregnancy poses risks to both mother and fetus. Maternal hypercalcemia can suppress the fetal parathyroid glands, leading to neonatal hypocalcemia at birth. Parathyroidectomy is generally considered safe during the second trimester for patients with significant hypercalcemia (Schnatz & Curry, 2002).
• Children and Adolescents: Pediatric PHPT is uncommon but is more frequently associated with hereditary syndromes (like MEN1 and MEN2A) and tends to present with more severe symptoms. Genetic testing is strongly recommended for all pediatric cases.
• The Elderly: In older people, the neuropsychiatric effects of hypercalcemia can be devastating, contributing to falls and functional decline. The decision for surgery must carefully weigh the benefits against the higher perioperative risks. For non-surgical candidates, cinacalcet can control hypercalcemia, and bisphosphonates can reduce fracture risk (Bilezikian et al., 2022).

Summary and Clinical Pearls: What Every Clinician Should Know

After this comprehensive exploration, I want to distill the most clinically actionable points:

• Always check serum calcium in patients presenting with fatigue, polyuria, polydipsia, depression, cognitive impairment, kidney stones, or osteoporosis.
• The combination of hypercalcemia and elevated (or inappropriately normal) PTH is the defining laboratory signature of primary hyperparathyroidism.
• Correct calcium for albumin and consider measuring ionized calcium in critically ill patients.
• Do not overlook vitamin D deficiency in the PHPT workup; it is common and masks disease severity.
• Rule out familial hypocalciuric hypercalcemia (FHH) with a 24-hour urine calcium and CCCR calculation before referring for surgery.
• Asymptomatic does not mean inconsequential—patients may have silent kidney stones, subclinical osteoporosis, and neurocognitive symptoms.
• Surgery is the only cure for primary hyperparathyroidism, but medical management with careful surveillance is a safe alternative for many.
• The integrative approach—combining internal medicine, chiropractic rehabilitation, and functional medicine—provides the most comprehensive management.
• Postoperative care is not the end—patients require long-term follow-up for bone density recovery, calcium homeostasis, and vitamin D optimization.

Conclusion: Addressing Calcium Chaos Through Integrative Excellence

The management of hyperparathyroidism is, at its core, an exercise in systems thinking. Addressing its diverse manifestations requires exactly the kind of multidisciplinary, integrative approach that we have built at Injury Medical Clinic PA in El Paso, Texas. Under the medical direction of Dr. Maria Guadalupe Cardenas, MD, and through my own work as a chiropractor, advanced practice nurse, and functional medicine practitioner, we offer our patients a unified clinical team that can simultaneously address the endocrinological, musculoskeletal, metabolic, and rehabilitative dimensions of this complex condition.

The story of Captain Charles Martel is a powerful reminder of what is at stake when calcium chaos is not managed promptly. A century later, with the tools of modern medicine, we have the capacity to give our patients an entirely different story. I am deeply committed to providing every patient who walks through our doors with access to that better story—one of early diagnosis, comprehensive management, and a genuine partnership in the lifelong pursuit of optimal health.

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